Thalidomide: A grim reminder of why we care about drug safety.
The entire world waits on pins and needles for a magic bullet to stop COVID-19 dead in its tracks. We cheer on researchers working around the clock to find a solution, a vaccine, or a cure. Despite our enthusiasm, we must take a cautious approach to medical research. Thalidomide’s history is a grim reminder of what can go wrong when a drug comes to market without proper clinical trials and oversight.
Marketed to pregnant women in the 1950–60s as a cure for morning sickness, thousands of babies suffered severe disfiguring abnormalities of the arms and legs from the unrecognized dangers of the drug.
“Those who do not remember the past are doomed to repeat it.” — George Santayana
Thalidomide, an anticonvulsant drug, was developed in the 1950s by a German pharmaceutical company Chemie‐Grunenthal. A side effect of the medication was drowsiness. In 1956, Germany and most of Europe licensed it as an over-the-counter sleep aid.
Thalidomide had another beneficial side effect, the reduction of pregnancy morning sickness. The drug quickly became popular among pregnant women suffering from the common first-trimester symptom of nausea. Heavily marketed and sampled in physician offices as safe, Thalidomide became one of the world’s most popular medications.
Nausea and vomiting in pregnancy, hyperemesis gravidarum, occurs in the first trimester. Fetal organ development also occurs during this gestational age. A medication that interferes with fetal organogenesis should be avoided during this critical time in a baby’s development.
During the clinical trials for Thalidomide, animal tests did not study the effects of the drug during pregnancy. Rigorous worldwide guidelines for pharmaceutical testing were not in place as they are today. The result was over 10,000 children were born with severe and sometimes deadly Thalidomide-related disabilities around the world.
Although the drug was studied in clinical trials, the effects on pregnant women were unknown. The medication was prescribed by doctors and used by women “off-label” under the false presumption of safety.
It took years for the evidence of profound limb and other effects on babies to be linked back to maternal Thalidomide exposure. Later research uncovered the one compound, CPS49, that caused the severe limb defects (phocomelia) associated with Thalidomide exposure. Along the way to discovery, many babies died in utero or were lost to early miscarriage.
The true number of babies affected by Thalidomide will forever remain unknown.
Primun non nocerere. Every first-year medical student learns this fundamental principle of bioethics. It means, “First, do no harm” All physicians are asked to consider the potential for harm before any medical intervention. When faced with a problem, one must weigh the benefits against the potential risks or unintended consequences.
Photo by Elena Mozhvilo on Unsplash
No matter how well-intentioned a treatment may be, one must always consider the unintended consequences. Medications have side effects. Surgical injuries occur. Weird and often unexpected outcomes show up during medical research. Viagra was originally developed for the treatment of high blood pressure until its side effect of inducing erections was discovered.
In clinical trials, the term for an unintended consequence is referred to as an “adverse event.” An adverse event is any untoward outcome experienced by a clinical trial patient.
An adverse event is documented, tracked, and traced regardless of a known causal relationship with the pharmaceutical or medical device being evaluated. Event tracking is a key tool in Good Clinical Practice guidelines to uncover unexpected outcomes and protect patient safety.
Patient safety comes first
Patient safety must be our priority to find a treatment for COVID-19. SARS-CoV-2 is a novel virus. This means the human race has never been exposed. We have no baseline immunity or protective antibodies. We do not have a vaccine or effective medication to treat it. Since we are all susceptible to Covid-19, our urgency to find an effective treatment is understandable.
Fear and panic fill our social media feeds. Click-bait headlines take us to untrustworthy news sites. We see our friends disregarding face cover recommendations. Some share false and inaccurate information. A lack of reliable information feeds worldwide anxiety.
Every day scientists learn more about SARS-CoV-2. But from a medical research perspective, we are starting from ground zero. In our desire to find a miracle cure, we can not throw caution to the wind.
Blindly endorsing Hydroxychloroquine is dangerous when not supported by validated scientific evidence. After the hype surrounding Hydroxychloroquine, the FDA had to release a statement regarding the potential danger of using the drug outside of the hospital setting or in clinical trials. Politicians discussing home cleaning agents forced Lysol to issue a warning not to inject or ingest disinfectants. We must be skeptical when Televangelists exploit our fear by peddling snake oil.
Doctors must remember our societal responsibility to provide scientific and validated care when using social media sites. Celebrity physicians like Dr. Oz, Dr. Phil, and Dr. Drew have millions of fans who interpret their musings as facts. Youtube removed a controversial California Urgent Care center owners’ video downplaying the risk of COVID-19 after the American College and Emergency Physicians and the American Academy of Emergency Medicine issues a joint statement against physician misinformation.
More than 100 tests for COVID-19 are coming to the market under the FDA Emergency Authorization Act. Each test will have different degrees of accuracy. We must exercise caution before public health policy gets ahead of the scientific understanding of antibody testing.
Research takes time. Anecdotal case reports and unpublished small cohort studies have value. These studies provide real-time data in an information vacuum to physicians in the field. A small study in New York yields interesting results regarding the use of heartburn medication in the treatment of COVID-19. These small clinical trials are only the first steps. They serve to identify the essential questions requiring further study in more robust trials. These studies do not mean we should all start taking medication for acid reflux.
The Food and Drug Administration oversight started with the passage of the 1906 Pure Food and Drugs Act, an effort to protect consumers against misbranded food and medications. Many may be frustrated by FDA oversight slowing down the process in COVID-19 research.
FDA oversight prevented Thalidomide from being approved in the United States. Dr. Frances Oldham Kelsey, an FDA medical officer, refused to approve Thalidomide due to a lack of clinical evidence regarding its safety despite heavy pressure from the pharmaceutical company. Her heroic and data-driven decisions saved thousands of babies.
First, do no harm
We must remember the legacy of Dr. Kelsey, value the FDA approval process, and respect Good Clinical Practice guidelines. Most countries in Europe approved Thalidomide for distribution at scale. Dr. Kelsey reviewed the available data and took action based on sound science.
We must take the same approach with COVID-19 Research. Case reports on Facebook should not trigger governmental actions. A small clinical trial in our Twitter feeds can not lead to changes in public policy. Doctors on Tik-Tok and Youtube should not determine when our economies reopen.
Even if a politician, religious leader or TV physician suggests it, do not drink, ingest or inject household cleaning products or disinfectants. Do not jump on the bandwagon after promising results from a small clinical trial or case report.
Allow the methodical scientific process to lead the way, and we find safe and effective treatments for COVID-19.
Blog Author: Dr. Jeff Livingston