Safety Assessment
Alan Hoberman

Recalling the Thalidomide Crisis

Being reminded of the past is a good time to reflect on how far research and regulatory requirements have come and where we need to go.

In 1957, thalidomide entered the German market as an over-the-counter remedy that men and women, including pregnant women, used as a sedative. Unfortunately, we know how this story ends. The drug caused fetal death and serious birth defects at the therapeutic dose in children born to mothers who took the drug. It also catalyzed the beginnings of the rigorous drug approval and monitoring systems used today by the US Food and Drug Administration to prevent birth defects.

The thalidomide story was briefly in the limelight recently with the death of Harold Evans, a former editor of the British-based Sunday Times and husband of Tina Brown. Harold took up the fight on behalf of families of some 90,000 babies who had died in spontaneous abortions and at least 10,000 who were born malformed because of thalidomide. He waged an aggressive campaign against the drug companies who marketed thalidomide, pursuing them through the English courts and eventually gaining victory in the European Court of Human Rights.

The death of Mr. Evans reminded me of Francis Kelsey, who died a few years earlier. Dr. Kelsey. a reviewer at the FDA during the 1960s, questioned the lack of data surrounding thalidomide and wondered specifically whether the drug was able to cross the placental barrier. Because of Dr. Kelsey, thalidomide never made it to market in the US. In different capacities, Evans and Kelsey elucidated the fact that a potential hazard may be different in an embryo or fetus than in the mother.

Thalidomide caused both internal and external structural malformations but this potential risk was not known to exist at the time. At the time, clinical trials did not even require FDA approval, nor were they subject to regulatory oversight. Since then our guidelines have done a good job identifying drugs and chemicals that might produce malformations in animals and by inference in humans. In these situations, drug manufacturers must provide a warning about use of the drug or exposure to chemical in pregnant women.

Our job as reproductive toxicologists continues to be to identify the hazard and assess the risk to humans. Drugs such as Accutane that are clearly teratogenic (produce malformations) and even thalidomide, are on the market, but we know to prevent the use of these products during pregnancy. We also know, from Dr. David Karnofsky, that any drug or chemical given at the proper dose and at the proper time during pregnancy can interfere with development of the conceptus. The hazard from these drugs or chemicals may be more than just the production of structural malformation. We know that other outcomes of toxicity to the conceptus include growth retardation as we see with cigarette smoking and functional deficits (lower IQ or mental retardation) as we see with alcohol. The effects of smoking and alcohol became clear after years of evaluating the children of mothers who smoke and/or drank during pregnancy.

But the concerns don’t end there. It begs the question: Are we missing effects other than structural in children of mothers taking other drugs or being exposed to chemicals? Maybe. The question also needs to be asked if we are we doing the kind of research designed to improve our testing so we can better identify all of the chemicals that need to be tested for these toxicities?

Properly conducted studies with trained technical staff, experienced Study Directors, measurement of exposure, and sufficient historical control data to account for the variation in the animals that we use for these tests provide confidence in our results. Testing at exposure levels that are relevant to human exposure is also critical. For all the chemicals that still need to be tested for developmental toxicity, we have to develop better and more translatable in vitro methods to determine the hazard to the conceptus.

Toward that end, various US governmental agencies, including the US Environmental Protection Agency (EPA), are funding research into artificial embryos and placentas, that along with organs-on-a-chip and various other cellular and subcellular models will hopefully, by 2035, allow us to quickly and accurately evaluate the potential hazard of any chemical or drug without the sole use of animals.

In the interim we need to continue to evaluate this hazard based on the best scientific guidance, the kind that was first developed after the thalidomide tragedy. Continued advances in molecular and developmental biology will hopefully allow us to understand the fate of every cell in the developing conceptus and the impact of any insult on that development, so that we never encounter another thalidomide tragedy.