“IN GENERAL- In conducting or supporting clinical research for purposes of this title, the Director of NIH shall, subject to subsection (b), ensure that— (A) women are included as subjects in each project of such research; and (B) members of minority groups are included as subjects in such research.”
Published in 1993, the NIH Revitalization Act marked a shift in healthcare generally and in clinical trials specifically, codifying the idea that all NIH-funded research needed to include minorities and women, including those of childbearing age. Now, in honor of the 30th anniversary of the NIH Revitalization Act on June 10, 2023, here are 10 facts to illustrate its significance – and the progress that still can be made.
Clinical trials test new healthcare treatments in actual human patients to determine the treatments’ effectiveness, side effects, safety, and ideal dosage amount, among others. While individual trials may differ, the National Institutes of Health (NIH) notes that, usually, Phase I trials (which first test the treatment for safety concerns or side effects) include about 20 to 80 participants, Phase II trials (which determine effectiveness and continue to study safety) include about 100 to 300 participants, and Phase III trials (which confirm effectiveness, monitor side effects, compare the tested treatments to other treatments, and help maximize safety and efficacy) include about 1,000 to 3,000 participants. Currently, the United States alone has 140,281 registered clinical trials.
2. $19 million
While devices, therapeutics, and other medical treatments can all go through clinical trials, those for new drugs tend to have some of the highest costs; their median price tag is $19 million for just the clinical trials alone. (Average research and development costs for drugs, meanwhile, can range from under $1 billion to over $2 billion.) Most of these massive expenses, however, are sunk costs: only about 12% of drugs that enter clinicals trials become available for commercial use.
3. 16 years
Despite the sheer number and costs of clinical trials, they still excluded a large part of the population for about 16 years. In 1977, the Food and Drug Administration (FDA) recommended excluding women of child-bearing age (those from ages 15 to 49) from participating in almost all early-phase clinical trials. The FDA was concerned about the risks to pregnant women or women who could become pregnant, especially after the consequences of thalidomide, which some scientists call the “biggest man-made medical disaster ever”.
In the 1950s, thalidomide was used to alleviate morning sickness, among other conditions – but wasn’t tested on pregnant women beforehand. Only after it was made commercially available did studies find that it led to increased rates of pregnancy loss and at least 10,000 cases of severe physical deformities in newborns, including in their bones, limbs, and organs. Up to 40% or 50% of affected babies died within months.
This tragedy influenced the FDA to pass the FDA Guidance General Considerations for the Clinical Evaluation of Drugs in 1977 and keep it in place for the next 16 years.
Following both reports that women were not adequately included in clinical trials and the growing awareness that women should be able to choose whether they want to participate in clinical trials themselves, the NIH Revitalization Act was passed in 1993. The goal was to include women and minorities in NIH-funded research, and, thus, help uncover any race- or sex-based effects that a medical treatment might have. But since NIH-funded research accounts for only 6% of all clinical trials, the reach of the NIH Revitalization Act remains limited – and some race- or sex-based effects still go unstudied.
For example, cardiovascular disease is the leading cause of mortality in women. But only 38% of participants in cardiovascular clinical trials are women and only 28% of clinical trials analyze data by biological sex, preventing researchers from knowing what results are sex-based or not.
As a result, men’s typical heart attack symptoms (chest pain or pressure, shortness of breath, and lightheadedness) — not women’s symptoms (chest pain but also flu-like fatigue, nausea, night sweats, and stomach pain) — are considered “typical” for a heart attack. Due to this male default, women are 50% more likely than men to receive the wrong diagnosis after a heart attack and to die the year following their heart attack.
“Serious male biases in basic, preclinical, and clinical research” also caused the FDA to withdraw 10 prescription drugs from the market between 1997 and 2000, 80% of which caused greater health risks in women than in men. Due to the lack of women in these drugs’ clinical trials, the sex-based effects weren’t revealed until after these treatments were commercially available, like in the case of thalidomide. And yet, despite the adverse effects of thalidomide in the 1950s and these eight other prescription drugs at the turn of the century, male bias continues to persist. A clinical trial for female Viagra, which was marked as the “pink pill” to emphasize its focus on women, had only two women out of its 25 total participants. Women who took the drug after it became available found it was minimally beneficial and linked to increased risks of sleepiness, dizziness, fatigue, and nausea.
One limiting factor for women’s and minorities’ clinical trial participation is the distrust they may already have of the medical system, which has historically excluded and dismissed them. One study found that women, across races, were more likely than men to report that a healthcare provider dismissed their concerns (21% vs. 12% respectively) or didn’t believe them (10% vs. 7% respectively). In fact, 20% of women who had a negative experience with a healthcare provider believed it was due to their gender.
38% of Black women, meanwhile, believed their negative experience with a healthcare provider was due to their race. A 2011 study of Black Americans, men and women alike, found participants didn’t necessarily trust their physicians who might be their very entry point into a clinical trial. Specifically, 25% of responders expressed a high level of doubt that their physician would be forthcoming with them or would stop their participation in a clinical trial if serious harm were anticipated. This distrust leads to reduced enrollments in clinical trials and limited data about any race-based medical effect, like those of carbamazepine (also known by its brand names Carbatro, Epitol, Equetro, or Tegretol). This epilepsy medication can cause a severe skin disorder in patients of Asian heritage with a particular gene variant: one that white patients don’t share.
This cycle of distrust and bias helps keep clinical trial participation to around 86% white and usually male. Women and minority participation in clinical trials has increased but is still lacking – especially since women are now 50% of the U.S population, and racial and ethnic minorities are about 40% – and healthcare products’ effectiveness subsequently remains tested on and calibrated for white men.
10. 30 years
Despite the challenges it has faced, the NIH Revitalization Act still has had a generally positive ripple effect on healthcare over the past 30 years. In 2016, the NIH passed the Sex as a Biological Variable Act to mandate that NIH-funded research must proportionally include female cells and tissues. In 2022, the FDA issued guidance for enrolling participants of underrepresented racial or ethnic groups to try to improve the diversity in clinical trials. And, even today, researchers and scientists are still trying to disprove the pervasive falsehoods that females behave more erratically than men due to their hormonal cycles and that including them would be more complicated and more costly than including men alone.
These initiatives recognize the significance of women and minority inclusion in clinical trials and the distrust and biases limiting them. In the process, they build off the NIH Revitalization Act, forward its legacy, and help it achieve the goals for clinical trial representation that it set out on June 10, 1993: 30 years ago.
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