FDA head explains decision to drop 'black box' warnings from menopause hormone treatment

Key Concepts

• Black Box Warning: A warning label on prescription drugs that indicates serious or life-threatening risks.
• Hormone Replacement Therapy (HRT): Medication used to treat symptoms of menopause by replacing hormones like estrogen.
• Systemic Estrogen: Estrogen that enters the bloodstream, typically taken as a pill or patch.
• Local Estrogen: Estrogen applied directly to a specific area, often as a cream.
• Women's Health Initiative (WHI) Study: A large study initiated in the early 2000s that led to concerns about HRT risks.
• Cardiovascular Disease: Diseases affecting the heart and blood vessels.
• Nitric Oxide: A molecule that helps keep blood vessel walls soft and healthy.
• Cognitive Decline: A decrease in mental abilities such as memory and thinking.
• Acetaminophen (Tylenol): A common pain reliever and fever reducer.
• Neurodevelopmental Disorders: Conditions affecting brain development, such as autism.
• Meta-analysis: A statistical analysis that combines the results of multiple studies.

FDA Announcement on Hormone Therapy Warnings

The U.S. Food and Drug Administration (FDA) has announced it will begin asking drug companies to remove "black box warnings" from hormones prescribed for menopausal symptom treatment. This decision stems from the FDA's belief that the warning, implemented in the early 2000s, has unnecessarily dissuaded millions of women from utilizing potentially beneficial medications.

Rationale for Removing Black Box Warnings

• Misinterpreted Study Results: The black box warning was initially placed on hormone therapy (HT) products following claims from researchers in the Women's Health Initiative (WHI) study, suggesting an increased risk of breast cancer. However, many experts now argue that this risk is not present for many candidates for menopause hormone therapy.
• Distorted Perception of Risk: FDA Commissioner Dr. Marty Makary stated that the warning, based on a "tragically misinterpreted study and results," has led to a distorted perception of risk for approximately 50 million women who have been denied, not offered, or convinced out of hormone replacement therapy.
• Profound Health Benefits: Dr. Makary highlighted significant benefits of HRT, including reducing the risk of cardiovascular disease and heart attacks, which are the leading cause of death in women. He emphasized that no study or clinical trial has ever shown an increased risk of breast cancer mortality with HRT.
• Addressing Historical Neglect of Women's Health: The FDA's action is framed as part of a broader effort by the current administration to ensure women's health issues receive the attention they deserve, which has historically been lacking.

Nuances in Estrogen Types and Risk-Benefit Ratios

The FDA's announcement applies to label changes for both local and systemic estrogen. However, some experts contend that this broad approach may be too encompassing, as the risk-benefit ratio differs between the two types.

• Systemic Estrogen: Taken in pill or patch form, it works through the bloodstream. A crucial nuance for systemic estrogen is the timing of initiation. If started more than 10 years after the onset of menopause (or after age 60), the risk-benefit ratio can invert, and most doctors do not prescribe it.
• Local Estrogen: Applied directly to an area, such as creams.

Long-Term Benefits of Systemic Estrogen

Maintaining continuous levels of intrinsic or exogenous estrogen through HRT is critical for preserving nitric oxide. Nitric oxide is essential for maintaining soft and healthy blood vessel walls, which may explain the observed dramatic drop in heart attack rates.

• Cardiovascular Benefits: One study from two years prior indicated a 48% decline in fatal heart attacks and a 30% decline in overall mortality.
• Skeletal Health: Significant reduction in the rate of bone fractures later in life.
• Cognitive Health: Reduced risk of cognitive decline.
• Symptom Relief: In addition to these long-term preventive elements, HRT effectively alleviates short-term menopausal symptoms like hot flashes, mood swings, night sweats, and weight gain.

Addressing Skepticism and the "Old Guard" in Medicine

While there is broad agreement on HRT's effectiveness for menopausal symptom relief, some experts express less certainty about its preventive elements, citing conflicting study results.

• "Old Guard" Dogma: Dr. Makary attributed lingering skepticism to an "old guard" in the medical establishment that "got HRT wrong" and created a "fear machine." He drew parallels to other instances where the medical field has been demonstrably wrong, such as the understanding of opioid addiction, saturated fat's impact on heart disease, and recommendations regarding early peanut butter introduction for children.
• Groupthink and Medical Mistakes: He characterized the collective misjudgment on HRT as potentially "one of the greatest mistakes in modern medicine," emphasizing that the data is now overwhelming, supported by systemic meta-analyses.
• OB/GYN vs. Primary Care: Doctors of obstetrics and gynecology (OB/GYNs), who are more familiar with prescribing hormones, have been at the forefront of a more accurate understanding of the literature. In contrast, some primary care physicians still hesitate to prescribe HRT due to perceived breast cancer risks, despite a lack of clinical trial evidence supporting increased breast cancer mortality.

Comparison with Acetaminophen Warning Label Change

The FDA's decision to remove warnings from HRT is contrasted with its simultaneous call for a label change regarding acetaminophen (Tylenol), citing a potential link between its use and autism. This has led to questions about the FDA's consistency in applying warning labels.

• FDA's Response to Perceived Inconsistency: Dr. Makary asserted that there is "no comparison whatsoever" between the two situations.
  • Acetaminophen and Pregnancy: The FDA includes information about known risks of medications during pregnancy. Studies have shown an association between acetaminophen use during pregnancy and neurodevelopmental disorders like autism. The Dean of Harvard Public Health believes there is a causal relationship, and a study from Mount Sinai and Harvard showed an association. This information, along with references to studies supporting and refuting the association, will be included in the label.
  • Hormone Replacement Therapy: Dr. Makary described the situation with HRT as being on a "totally different level." The black box warning has instilled fear, preventing women from accessing a therapy that may offer profound long-term health benefits, potentially rivaling antibiotics or vaccines in improving women's health outcomes on a population level.

Disagreement on Harvard Dean's Statement

A point of contention arose regarding the interpretation of statements from the Dean of Harvard Public Health concerning acetaminophen and autism.

• Dr. Makary's Interpretation: Dr. Makary cited the Dean as stating there is a "causal relationship" between prenatal acetaminophen exposure and neurodevelopmental disorders. He claimed that while the Dean may have issued a generic statement recently, he was on record in 2018 stating a causal relationship and was an author of a study showing an association.
• Counterpoint: The interviewer stated that they reached out to Harvard, and the Dean's statement was that "biological evidence supports the possibility of a causal relationship." The interviewer also noted that the Dean's recent public statement was generic.

Basis for FDA Decisions

The discussion highlighted that the HRT warning change is based on ending "fear-mongering," while the acetaminophen label change is based on scientific findings of an association, with some experts suggesting a causal link. Dr. Makary reiterated that 20 studies show an association and that the Dean of Harvard School stated there is a causal relationship, urging the interviewer to contact Harvard's communications office for confirmation. He characterized the Dean's recent public statement as a retreat from his earlier, more definitive stance.

Conclusion

The FDA's decision to remove black box warnings from hormone replacement therapy signifies a shift in understanding, driven by a re-evaluation of past studies and a recognition of the significant health benefits HRT can offer menopausal women. This move aims to correct a historical misperception of risk and ensure women have access to treatments that can improve their long-term health outcomes. The FDA maintains that this decision is distinct from its approach to acetaminophen warnings, which are based on different scientific evidence and concerns.