Mark B. McClellan, M.D., Ph.D.
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
Dear Commissioner McClellan:
The Food and Drug Administration’s (FDA) September 9, 2003, announcement of a “Collaborative Campaign to Inform Women About Menopausal Hormone Therapy” does a disservice to women by promoting drug information that is incomplete and thus potentially dangerous. Rather than promoting incomplete information, you should seek to ensure that women ask for and receive the FDA-approved patient information that is required by regulation to be distributed with each prescription for a non-contraceptive estrogen product.
To assess the adequacy of the Collaborative Campaign’s information, posted on the Department of Health and Human Services’ (DHHS) National Women’s Health Information Center website, we compared that information to the FDA-approved patient information required for the most frequently dispensed estrogen product in the U.S., conjugated estrogens (Premarin) produced by Wyeth Pharmaceuticals of Philadelphia. (In the 1997 Action Plan for the Provision of Useful Prescription Medicine Information, DHHS accepted information consistent with or derived from a drug’s professional product label as part of the definition of “useful scientifically accurate” consumer drug information.) That comparison shows several gaping holes in the website information. Astonishingly, the DHHS website does not even include a link to the FDA-approved patient information.
Information in Black Box Warning Not Prominently Displayed
A black box warning is the strongest type of warning that the FDA can require for a drug and is generally reserved for warning prescribers about adverse drug reactions that can cause serious injury or death. The Action Plan guidelines, now echoed in FDA regulation, state that black box warning information should appear at the beginning of written information intended for patients, although not necessarily in a box. This guideline was adopted for two reasons: (1) to require that black box warning information appear at the beginning of the professional product labeling and not to require the same location for information written for consumers would be illogical; and (2) to ensure that risk information about a drug would be the first thing read by consumers to counter the frequent overstatement of benefits and minimization of risks put forth by pharmaceutical manufacturers.
The information below appears at the beginning of the FDA-approved patient information for Premarin:
What is the most important information I should know about Premarin (an estrogen mixture)?
- Estrogens increase the chances of getting cancer of the uterus.
Report any unusual vaginal bleeding right away while you are taking Premarin. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.
- Do not use estrogens with or without progestins to prevent heart disease, heart attacks, or strokes.
Using estrogens with or without progestins may increase your chances of getting heart attacks, strokes, breast cancer, and blood clots. You and your healthcare provider should talk regularly about whether you still need treatment with estrogens.
In the Collaborative Campaign information being touted by DHHS, this “most important information” appears as the sixth topic, after the benefit information and other information about hormones and menopause. On this point alone, the information from the Collaborative Campaign fails to meet the FDA-endorsed Action Plan’s definition of useful, scientifically accurate drug information for patients.
Contraindications to the Use of Hormone Replacement Therapy Not Prominently Displayed
The Collaborative Campaign website has a link to an FDA Fact Sheet in which the conditions under which women should never use hormone replacement therapy (contraindications) are displayed in a sidebar under a list of benefits of the hormones. In fact, these benefits are mentioned twice in the Collaborative Campaign information. In contrast, the FDA-approved Premarin information for patients prominently advises not to take Premarin if you:
- have unusual vaginal bleeding.
- currently have or have had certain cancers. Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer, talk with your healthcare provider about whether you should take Premarin.
- had a stroke or heart attack in the past year.
- currently have or have had blood clots.
- are allergic to Premarin tablets or any of its ingredients.
- think you may be pregnant (bold in original).
No Mention of Symptoms of Hormone-Induced Illness or of Steps to Take if Such Symptoms Occur
The FDA-approved Premarin information tells women to be alert for the following warning signs of serious, hormone-induced adverse drug reactions and instructs them to call their healthcare provider “right away” if any of the following occur:
- Breast lumps
- Unusual vaginal bleeding
- Dizziness and faintness
- Changes in speech
- Severe headaches
- Chest pain
- Shortness of breath
- Pains in your legs
- Changes in vision
This information is totally missing from the Collaborative Campaign information.
No Mention of Alternatives to Hormone Replacement for the Prevention of Osteoporosis
The FDA-approved patient information for Premarin carries this statement: “If you use Premarin only to prevent osteoporosis from menopause, talk with your healthcare provider about whether a different treatment or medicine without estrogrens might be better for you.” This information, too, is missing from the Collaborative Campaign information.
Possible Future Addition to the Website
The Collaborative Campaign information correctly states that women should not take hormone replacement therapy in the hopes of preventing memory loss or Alzheimer’s Disease. In fact, data from the Women’s Health Initiative study suggest that, if anything, hormone replacement therapy use in this randomized trial was associated with increased risk for “probable dementia.” Presumably, the FDA intends to change its professional labeling to reflect this; we expect that the patient information and the Collaborative Campaign material will be changed simultaneously to convey this risk.
Incomplete information is not accurate information. The agency is on record saying that one of its priorities is increasing the amount of accurate information conveyed to consumers about FDA-regulated products. You yourself recently said:
“I consider it a public health hazard when people are misled by false claims.” Government-provided information that succinctly states the few benefits of hormone replacement therapy while omitting the very information that the FDA mandates by law in other contexts fails to provide accurate drug information. Indeed, were Wyeth to distribute information as unbalanced as that of the Collaborative Campaign, you would be empowered to take legal action against the company.
How could DHHS approve a campaign that would be in violation of its daughter agency’s requirements? A press report states ” that there was direct and indirect pressure on the FDA from the largest maker of hormone products, Wyeth Pharmaceuticals” during the development of the Collaborative Campaign. The entire campaign has a strong resemblance to advertising material. The opening webpage on the site contains no substantive information whatsoever. Instead, the page offers only a collage of photographs of attractive seniors frolicking in flowery fields and riding bicycles (see attached). One must then click on this image to reach the misleading information on the website. This page, which is unnecessary from a web design perspective, should simply be eliminated.
We urge you to correct this situation as soon as possible by replacing the Collaborative Campaign information with patient information based on the current FDA-approved patient information for Premarin.
Larry D. Sasich, Pharm.D., M.P.H.
Peter Lurie, M.D., M.P.H.
Public Citizen’s Health Research Group
 Department of Health and Human Services, Food and Drug Administration. FDA Launches Collaborative Campaign to Inform Women About Menopausal Hormone Therapy, September 9, 2003. Available at www.fda.gov/bbs/topics/NEWS/2003/NEW00938.html, accessed September 12, 2003.
 21 CFR 310.515.
 Food and Drug Administration approved professional product and patient information Labeling for conjugated estrogens (Premarin). Available at www.wyeth.com/content/ShowLabeling.asp?id=131, accessed September 12, 2003. FDA regulation requires that patient information labeling “shall be scientifically accurate and shall be based on, and shall not conflict with, the approved professional labeling for the product.” 21 CFR 208.20.
 Action Plan for the Provision of Useful Prescription Medicine Information presented to The Honorable Donna E. Shalala, Secretary of the Department of Health and Human Services by the Steering Committee for the Collaborative Development of a Long-Range Actions Plan for the Provision of Useful Prescription Medicine Information, December 1996.
A Steering Committee met seven times between September 18, 1996 and December 4, 1996 in the Washington DC area in a very contentious debate to develop The Action Plan. Consumer groups advocated for the mandatory distribution by pharmacists of FDA regulated drug information similar to regulations first proposed by the agency in 1979. Consumer groups noted that the private sector had pursued a failed paradigm since the inception of the National Council on Patient Information and Education (NCPIE) in 1982 that has not provided useful information to prescription drug consumers. Entities representing the drug industry, pharmacy and medicine, and commercial information vendors pressed for the status quo ? voluntary distribution, voluntary quality standards, no oversight, and no FDA involvement.
 21 CFR 208.
 Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003;289:2651-62.
 Kaufman M. FDA Offers Guidance On Hormone Therapy, Washington Post, September 10, 2003, p. A3.