How Sex Disparities in Clinical Drug Trials Hurt Women

Pharmaceutical trials are rigorous and comprehensive…right?  Before approving a drug for market, the Food and Drug Administration (“FDA”) requires that they be tested on lab animals (usually mice) and then on human test subjects. Some of these studies are government-funded and run by the National Institutes of Health (NIH), but most are done by the private pharmaceutical companies. The FDA’s Center for Drug Evaluation and Research then reviews the study’s data and, if convinced that the drug’s benefits outweigh the risks, approves the it.  Doctors can then begin prescribing the drug.

The FDA touts that Americans benefit from the “safest and most advanced pharmaceutical system in the world.”  But it’s perhaps more accurate to say that American men benefit from that exceptional pharmaceutical system.  Although women consume more pharmaceuticals than men, they comprise a minority of clinical trial test subjects and are at twice the risk for adverse drug reactions. Those who advocate for scientific accountability of sex differences in drug studies argue that the pharmaceutical industry lacks a commitment to women’s safety.

Why not include women?

Women’s hormone fluctuations are often considered a “confounding variable” – a fact that both excludes them from much clinical research, but also a crucial consideration for prescribers.  Research has shown that drugs like opioid painkillers, antidepressants, and anticonvulsants are metabolized differently in men and women.  Further, new research shows that drugs taken exclusively by women (like birth control pills) may interact negatively with common medications like antidepressants.

In the 1970s, the FDA banned women of childbearing age from drug trial participation.  After a morning sickness drug was found to cause birth defects, the FDA feared that their inclusion in drug trials was too risky.  This remained the rule until 1993, when the NIH Revitalization Act required that women be included in NIH trials.  Problem solved?  Not quite.  Only about 10% of drug trials are run by NIH; the remaining 90% are run and funded by the drug companies, who were not bound by the new law.  As of 2001, 66% of drug trials still excluded women.  Making matters worse, even the 33% of trials that did include women typically failed to collect sex-specific adverse reaction data, and if they did, the data was rarely analyzed.

The scope of this problem is not limited to human test subjects; scientists also prefer male mice.  In late 2014, the NIH mandated that all grant applications for research that will include lab mice must explain how the scientists plan to account for the impact of their research on both sexes.  However, most trials are still run by the pharmaceutical industry, so it isn’t clear if this will have a demonstrable impact.

Often, drugs that are pulled from the market have had a disproportionately negative impact on women.  Some studies show that 80% of pulled drugs’ adverse reactions were more dangerous for women.  And these harmful effects weren’t discovered until women actually used these drugs (which didn’t happen until the drugs were introduced to the public).  Examples of drugs that posed a greater threat to women include Seldanea, an antihistamine that caused a potentially fatal irregular heartbeat; Posicor, a cardiovascular drug, caused lowered heart rate in elderly women; and Rezulin, a diabetes medication, caused liver failure.

Over-the-counter (OTC) drugs carry similar but largely-unknown risks for women.  Studies show that Acetaminophen (Tylenol’s active ingredient) is metabolized 60% slower by women than by men, creating a risk for liver failure or overdose, but the bottle doesn’t warn women to adjust dosage.  And flu shots? Women require just half of the adult dose, yet they receive the same vaccines as men.

One of the most renowned cases of is that of Ambien, a popular sleeping pill.  Approved in 1992, the drug is now prescribed about 40 million times per year.  Women are more likely to be impacted by sleep disorders, but the drug’s testing included only male subjects.  In 2014, driving simulation tests revealed that the drug was lingering in their bloodstream the next morning.  The FDA cut the safe dose for women in half.  However, it turns out that the FDA knew of the problem in 1992, when it discovered that the drug was 45% more concentrated in women’s blood.

In an interview with The Guardian, Dr. Paula Johnson of Brigham and Women’s Hospital in Boston said: “I’m not sure how … there’s not more attention to this across all fields, disciplines, journals, and so forth.  No one wants to call it sexism but where else is it okay to ignore the basic facts? I think you have to wonder about that.”

The Take-away

Are your female patients struggling with adverse effects to medication after medication?  Are they taking a long-ago approved drug while using contraception? The decades-long failure to adequately include women in drug trials has created sometimes unpredictable side effects.  It’s crucial that providers validate and hear these complaints of negative side effects.  Your patient is experiencing real symptoms, and dismissing their complaints will only cause the patient-provider relationship to deteriorate.

A few reminders:

• Check, double-check, and triple-check drug interactions.
• Routinely review reported adverse effects in the NIH DailyMed database.
• Providers and patients should report adverse effects to the FDA’s MedWatch.
• Remind patients that they should tell you about adverse effects, and explain what symptoms should prompt an emergency room visit.

© 2017 Jackson LLP
Written by partner Erin Jackson, with research assistance from Jackson LLP’s intern, Caroline C

Questions? Email Erin Jackson at erin@jackson-legal.com.  Remember that our blog is never a substitute for legal advice..

Read more:

Michelle Llamas, How the FDA Let Women Down, Drugwatch.org.

Amy Westervelt, The medical research gender gap: how excluding women from clinical trials is hurting our health, The Guardian, (Apr. 2015).

Allison Eck, U.S. Government Will Require Sex Equality for Lab Mice, PBS Nova Next.

Alyson McGregor, TEDx, Why medicine often has dangerous side effects for women.

John Naish, The everyday medicines that make women ill because they have only been tested on MEN, Daily Mail (Nov. 2012).

Melinda Wenner Moyer, Drug Problem: Women Aren’t Properly Represented in Scientific Studies, Slate (2010).

Roni Jacobson, Psychotropic Drugs Affect Men and Women Differently, Scientific American.

This blog is made for educational purposes and is not intended to be specific legal advice to any particular person. It does not create an attorney-client relationship between our firm and the reader. It should not be used as a substitute for competent legal advice from a licensed attorney in your jurisdiction.