Have you ever heard of the concept of health equity? It is related to attaining equal opportunities for good health and high-quality health care for everybody. It sounds too good to be true, right? While it may be difficult, it is certainly achievable if individuals and society address multiple issues, including historical and social ones such as the under-representation of females in clinical trials. Let us explore this multifaceted topic in depth.
Biological Differences
Biologically speaking, females and males have varying anatomy (the structure of the body) and physiology (how the human body works). As such, the effect of a drug on the body differs (pharmacodynamics). These differences lead to dissimilar therapeutic and adverse effects of a drug. For certain syndromes, like long QT syndrome (a heart rhythm condition that can potentially cause fast, chaotic heartbeats), females are at higher risk. Females also have a higher incidence of some drug-induced toxicities and allergic reactions.
The effect of a drug on the human body (pharmacokinetics) and its concentration also play a vital role. Different factors, like the ratio between the drug administered in the body to the drug concentration in the plasma (volume of distribution), and the ratio of the elimination rate of a drug to the drug concentration in the blood (clearance), are dependent on body weight. Generally, males weigh more than females so they require a higher dosage according to their body, yet few drugs are dosed according to body weight.
Sex differences also affect the regulation of chemical reactions by biological catalysts (enzymatic activity), and the removal of nitrogenous wastes such as urea, salts, and excess water in urine (renal excretion). Moreover, the process that kidneys use to filter excess fluid and waste products out of the blood into the urine-collecting tubules of the kidney, so they may be eliminated from the body (glomerular filtration), is also impacted.
History
From 1938, Diethylstilbestrol, a synthetic hormone, was given to approximately 200,000 to 400,000 Canadian women to avoid miscarriages. It was later found to have harmful effects on their daughters, reducing fertility and causing adenocarcinoma (a cancer that starts in the mucus-producing glandular cells of the body) of the vagina. Another medication, Thalidomide, was used in the late 1950s and early 1960s as an off-label prescription for the treatment of morning sickness in pregnant women. In 1961, it was found that this drug interfered with normal child development, leading to conditions like phocomelia, resulting in shortened, absent, or flipper-like limbs. After these events, in an attempt to protect all fetuses from unknown side effects of drugs, all fertile women were banned from participating in clinical trials, whether or not they were pregnant.
In 1975, the National Commission for the Protection of Human Subjects and Biomedical and Behavioral Research brought forward a new rule which declared pregnant women as vulnerable research subjects. In 1977, the USFDA (United States Food and Drug Administration) introduced a guideline “General Considerations for the Clinical Evaluation of Drugs” in which they essentially banned fertile women from being included in early-phase clinical research, except for life-threatening conditions. Although this policy was supposed to be only for women of childbearing years and early phases of clinical trials, it was construed to all women being ruled out from all pharmaceutical research for almost two decades.
While there has been progressive improvement in recent times, the inclusion of women in certain heart diseases and cancer trials is concerning. The study Participation of Women in Clinical Trials: Not Yet Time to Rest on Our Laurels showed the underrepresentation of women (24%) in ischemic heart disease (IHD) and heart failure trials, the most common conditions in females. Also, the study Exclusion of Elderly People from Randomized Clinical Trials of Drugs for Ischemic Heart Disease sheds light on the exclusion of elderly females in trials of drugs for IHD even though it is most prevalent in their age group. Additionally, a study, Representation of Minorities and Women in Oncology Clinical Trials: a Review of the Past 14 Years, showed the persistent underrepresentation of females in trials for melanoma (35%), lung (39%), and pancreatic (40%) cancers.
According to the study, Exclusion of Pregnant Women from Industry-sponsored Clinical Trials, out of 558 Phase IV trials, only 1% were designed for pregnant women. It also showed that excluding pregnant women was a common occurrence in 95% of the cases. Another study, Evolving Knowledge of the Teratogenicity of Medications in Human Pregnancy, evaluated all the medications approved by the FDA from 1980 to 2010. It was discovered that 91% of these drugs did not have adequate information about their use and risks during pregnancy.
Consequences
Women are more susceptible to adverse side effects of medications as drug dosages are usually based on studies conducted on males according to research from the University of California, Berkeley, and the University of Chicago. “When it comes to prescribing drugs, a one-size-fits-all approach, based on male-dominated clinical trials, is not working, and women are getting the short end of the stick,” said the study’s lead author Irving Zucker, a professor emeritus of psychology and integrative biology at UC Berkeley.
Perusing the list of drugs withdrawn by the USFDA because of severe and potentially life-threatening side effects from 1997 to 2000, it is seen that out of the 10 drugs withdrawn, four cases were due to a side effect, torsade de pointes (associated with a prolonged QT interval), which predominantly affects females. An in-depth analysis by Prendergast and Zucker of several medical journals discovered evidence of a drug dose gender gap for 86 different medications approved by the USFDA, including antidepressants, cardiovascular and anti-seizure drugs, and analgesics, among others. In more than 90% of the cases, women suffered worse adverse effects like nausea, seizures, hallucinations, cognitive deficits and cardiac anomalies.
Due to the lack of research and knowledge, a challenging relationship started between physicians and female patients. Physicians would hesitate to prescribe drugs, give delayed diagnoses, or give women less aggressive treatments as compared to men. Looking into heart diseases, it was uncovered that women were less likely to be offered invasive surgical procedures like coronary artery bypass surgery (to restore normal blood flow to an obstructed artery). Moreover, lower survival rates have been detected in women diagnosed with Acquired Immunodeficiency Syndrome (AIDS) due to delayed identification and less aggressive treatment. Also, females with renal diseases faced hardship in gaining access to dialysis and transplantation. Females also received delayed diagnoses of lung cancer and cardiovascular disease, leading to morbidity and mortality.
Conclusion
As evident from the above discussion, there is a severe deficit of research and knowledge about the effects of various medications on the female body. Industry and governments should introduce new policies and closely monitor clinical trials to ensure equal participation of all sexes of diverse age groups so that no specific category suffers adverse effects from numerous medications. There is a need for serious changes in the medical system to provide health equity to all citizens, regardless of their sex.