Scientifically Speaking | The consequence of excluding women from drug trials
If a drug is not cleared rapidly, it can result in an adverse drug reaction resulting from overdose. It has been reported that women are twice as likely to suffer from adverse drug reactions than men
Adverse drug reactions are unwanted, harmful effects of taking drugs. In the United States (US) alone, where the Food and Drug Administration (FDA) documents these effects, they are the fourth leading cause of death. Around half of these adverse reactions may be preventable. But often the risks are not known because diverse populations were not included in clinical trials that led to the approval of these drugs.
Microscope and drug experiment for antiviral, antibacterial, probiotic in scientific laboratory (Getty Images/iStockphoto)
The disparities are stark. Historically, most clinical trials conducted in the US where many medications originate included only white males. Until 1993, the FDA considered women a special subgroup of patients, leading to their exclusion from most clinical trials. Many of the reasons given for excluding women from trials were paternalistic.
Men and women are biologically different, and these differences are reflected in how fast we clear drugs from our bodies. If a drug is not cleared rapidly, it can result in an adverse drug reaction resulting from overdose. It has been reported that women are twice as likely to suffer from adverse drug reactions than men.
In 1988, most trials were conducted on men, though women took 80% of the drugs on the market at the time. By one estimate, even as late as 2001, two-thirds of trials excluded women.
This lack of participation and knowledge has led to serious health effects. For example, the sleep aid, Zolpidem, caused prolonged and excessive drowsiness in women who were prescribed the initial recommended doses. In 2009, an American woman who had taken the drug hit two people while driving. She was not alone. Millions of women took a higher dose of a prescription drug because they had been discounted during the drug approval process. The dosage of Zolpidem for women was halved in 2014 because it was finally acknowledged that women clear the drug from their bodies more slowly. With broader and earlier oversight, this delay could have been prevented.
The dosage change for Zolpidem represents one example of a revised dosing regimen, but there’s limited data on the broader outlook in women for many other approved drugs.
Pregnant women are an important subset of the population. Many take medications during their pregnancy, but here also clear information on safety is not always made available. For example, two months ago, a statement published in the journal Nature Reviews Endocrinology noted that paracetamol exposure during pregnancy should be minimised due to the risk of foetal development defects. The statement, which was supported by 91 clinicians, scientists, and health professionals urged for broader global awareness of risks.
Women report that they consume more painkillers like paracetamol than men do. Paracetamol is a safe drug, but paracetamol is cleared in women more slowly than it is in men. Where is the public awareness of this difference? With people popping in pills of paracetamol for anything from pain to fever, it remains one of the most widely consumed drugs in the world.
This is not to say that the design of clinical trials hasn’t improved. It has. Most clinical trials these days are set up to be more inclusive of the general population that might benefit from the drugs and vaccines (and might also suffer from their adverse effects). Participation of diverse groups is encouraged. For example, for the Covid-19 vaccines that were approved, care was taken to include people in different populations. But this must extend to all trials and to all phases of medical research.
What can be done about all the drugs that are already approved and on the market? Since women were excluded from clinical trials for many of these drugs, those trials are unlikely to be repeated again. One way to gain meaningful information is to gather and analyse real-world data on effectiveness and adverse reactions that have been reported. In the US, the FDA maintains a database of around nine million patients with adverse reaction reports. This is a treasure-trove of information that can be sorted by gender, age, and other characteristics.
Technology can help to sort through this important data. Last year, two researchers at Columbia University, Payal Chandak and Nicholas Tatonetti, created a machine learning algorithm that accurately picks out adverse effects in women and men by looking at half a century of FDA reports. They published their findings in the journal Patterns.
Scientific and medical research is conducted by people, and people bring their views, preferences, and biases. To create a more equitable health care system, women and other traditionally underrepresented groups must be included in the approval and post-approval evaluation process for drugs, medical devices, and vaccines. The health of the world depends on it.
Anirban Mahapatra, a microbiologist by training, is the author of COVID-19: Separating Fact From Fiction.
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