Ursula A. Campbell
Senior Director
Wyeth Pharmaceuticals Inc.
P.O. Box 8299
Philadelphia, PA 19101

RE:  NDA# 004782
       Premarin® (conjugated estrogens tablets, USP)
       MACMIS# 18956

Dear Ms. Campbell:

As part of its routine monitoring and surveillance program, the Division of Drug Marketing, Advertising, and Communications (DDMAC) of the U.S. Food and Drug Administration (FDA) has reviewed patient testimonial videos (testimonials located on the homepage of the Premarin website (www.Premarin.com) for Premarin (conjugated estrogens tablets, USP) (Premarin). The testimonials are false or misleading because they overstate the efficacy of Premarin and minimize the serious risks of the drug product. Thus, the testimonials misbrand the drug in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a) & (n). See 21 CFR 202.1(e)(6)(i); & (e)(7)(viii).

Background

The INDICATIONS AND USAGE section of the FDA-approved product labeling (PI) for Premarin states (in pertinent part) that Premarin therapy is indicated in the:

•  Treatment of moderate to severe vasomotor symptoms due to menopause.

•  Treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.

Premarin is associated with a number of serious risks. The PI for Premarin includes a Boxed Warning concerning the risk of endometrial cancer, cardiovascular disorders, and probable dementia. The PI also contains numerous contraindications, including undiagnosed abnormal genital bleeding, known, suspected, or history of breast cancer except in appropriately selected patients being treated for metastic disease, known or suspected estrogen-dependent neoplasia, active deep vein thrombosis, pulmonary embolism or a history of these conditions, active or recent (within the past year) arterial thromboembolic disease (for example, stroke, myocardial infarction), liver dysfunction or disease, known hypersensitivity to any of the ingredients in Premarin, or known or suspected pregnancy. In addition, the PI also contains several warnings and precautions regarding gallbladder disease, hypercalcemia, visual abnormalities, hype rtrig lyce ride m ia, cholestatic jaundice, and hypothyroidism. The most common adverse reactions associated with Premarin include headache, breast pain, irregular vaginal bleeding or spotting, stomach/abdominal cramps, bloating, nausea and vomiting, hair loss, fluid retention, and vaginal yeast infection.

The CLINICAL STUDIES section of the PI includes the following information regarding Premarin’s effects on vasomotor symptoms:

In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, a total of 2,805 postmenopausal women (average age 53.3 ± 4.9 years) were randomly assigned to one of eight treatment groups, receiving either placebo or conjugated estrogens, with or without medroxyprogesterone acetate. Efficacy for vasomotor symptoms was assessed during the first 12 weeks of treatment in a subset of symptomatic women (n = 241) who had at least seven moderate to severe hot flushes daily, or at least 50 moderate to severe hot flushes during the week before randomization. Premarin (0.3 mg, 0.45 mg, and 0.625 mg tablets) was shown to be statistically better than placebo at weeks 4 and 12 for relief of both the frequency and severity of moderate to severe vasomotor symptoms. Table 2 shows the adjusted mean number of hot flushes in the Premarin 0.3 mg, 0.45 mg, and 0.625 mg and placebo treatment groups over the initial 12-week period.
 

a: Based on analysis of covariance with treatment as factor and baseline as covariate. Overstatement of Efficacy

Promotional materials are misleading if they represent or suggest that a drug is better or more effective than has been demonstrated by substantial evidence or substantial clinical experience. The homepage of the Premarin website presents testimonials made by five women (Connie, Rochelle, Maureen, Mary and Jeanne) about their experiences with treatment on Premarin. The testimonial by Mary includes the following statements:

•  “I said, ‘How would being on Premarin affect me?’ She [Mary’s physician] said, ‘You’re not going to go through menopause. You won’t have hot flashes. You won’t have any type of discomfort. And it would actually circumvent being on menopause at all.’ And I said, ‘Great.’”

•   “After surgery, for those 4 or 5 days that I was without any type of hormone therapy, I had some sensations that I’m really grateful I’m not going to go through. After a few days when the hormone therapy started to get into my system, it was gone.”

These claims seriously misrepresent what is known about the efficacy of Premarin. Mary’s statements misleadingly imply that Premarin will eliminate all hot flashes, discomfort, and other symptoms associated with menopause and that Premarin will “circumvent being on menopause at all.” These statements significantly exaggerate what was demonstrated in the clinical trials for Premarin. According to Table 2 of the Clinical Studies section of the PI for Premarin, patients taking 0.625 mg, 0.45 mg and 0.3 mg of Premarin experienced a mean of 0.75, 2.32 and 2.52 hot flushes per day at 12 weeks, respectively. FDA is not aware of substantial evidence or substantial clinical experience to support the testimonial claims made by Mary. While Mary’s statements may be an accurate reflection of her own experience, the personal experience of a Premarin patient such as Mary does not constitute such evidence. If you have any data to support these claims, please submit them to FDA for review.

The testimonial for Jeanne includes the following claims:

•  “It for me was an issue between my husband and myself . . . the vaginal dryness was very uncomfortable for me. . . . I went to my doctor. She put me on Premarin. She put me on the lowest dose. I noticed the changes immediately. I didn’t experience any more dryness, any vaginal dryness. That was just gone.” (emphasis added)

These claims misleadingly overstate the efficacy of Premarin by implying that Premarin has been shown to immediately eliminate all vaginal dryness associated with menopause. We note that data for the Health and Osteoporosis, Progestin and Estrogen (HOPE) study was submitted to support the safety and efficacy of multiple doses of oral Premarin for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. However, the HOPE study does not support the claims that Premarin will immediately eliminate all vaginal dryness. Furthermore, estrogens, including Premarin, require an interval of time to reverse the signs and symptoms of vaginal atrophy. FDA is not aware of substantial evidence or substantial clinical experience to support the testimonial claims made by Jeanne. While Jeanne’s statements may be an accurate reflection of her own experience, the personal experience of a patient such as Jeanne does not constitute such evidence. If you have any data to support these claims, please submit them to FDA for review.

Furthermore, the testimonials include the following claims:

•  “My life after Premarin became absolutely different. . . . I got up feeling like the day is better.” (Connie)

•  “I started feeling very much alive again.” (text next to video of Rochelle’s testimonial)

•  “PREMARIN brought my life back into a normal balance and I thought it made it more bearable.” (text next to video of Jeanne’s testimonial)

These claims misleadingly overstate the efficacy of Premarin by implying that treatment with Premarin will improve a patient’s overall physical and emotional functioning, including “feeling very much alive” and bringing “life back into a normal balance.” FDA is not aware of substantial evidence or substantial clinical experience to support patient-reported outcomes such as those included in these testimonials. The personal experiences of these patients do not constitute such evidence. In fact, this drug carries many potential risks (please refer to the Background section that summarizes the Boxed Warning and other risks) that can have a significant negative impact on a patient’s overall functioning. If you have any data to support such claims, please submit them to FDA for review.

Minimization of Risk Information

Promotional materials are misleading if they fail to present information about risks associated with a drug with a prominence and readability reasonably comparable to the presentation of information relating to the effectiveness of the drug, taking into account all implementing factors such as typography, layout, contrast, headlines, paragraphing, white space, and any other techniques apt to achieve emphasis. The testimonials minimize the risks of Premarin by failing to convey any risks associated with Premarin during these audio-visual presentations. Specifically, these colorful, audio-visual testimonials present five women who share their positive experiences with Premarin, during which they make numerous efficacy claims (as noted above). In contrast, risk information for Premarin is relegated to the bottom portion of the webpage below the testimonials in read-only text format, where it is unlikely to draw the viewer's attention. The audio-visual testimonials omit any discussion of serious risks, such as contraindications, warnings, and precautions associated with Premarin. Therefore, this overall presentation misleadingly minimizes the serious risks associated with Premarin because it fails to convey this important risk information with a prominence and readability reasonably comparable to the claims of effectiveness. The overall effect of this presentation undermines the communication of important risk information, misleadingly suggesting that the drug is safer than has been demonstrated by substantial evidence or substantial clinical experience.

Conclusion and Requested Action

For the reasons discussed above, the testimonials misbrand Premarin in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a) & (n). See 21 CFR 202.1(e)(6)(i); & (e)(7)(viii).

DDMAC requests that Wyeth Pharmaceuticals Inc. immediately cease the dissemination of violative promotional materials for Premarin such as those described above. Please submit a written response to this letter on or before September 13, 2010, stating whether you intend to comply with this request, listing all violative promotional materials for Premarin such as those described above, and explaining your plan for discontinuing use of such materials.

Please direct your response to the undersigned at the Food and Drug Administration, Center for Drug Evaluation and Research, Division of Drug Marketing, Advertising, and Communications, 5901-B Ammendale Road, Beltsville, MD, facsimile at 301-847-8444. In all future correspondence regarding this matter, please refer to MACMIS# 18956 in addition to the NDA number. We remind you that only written communications are considered official.

The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibility to ensure that your promotional materials for Premarin comply with each applicable requirement of the Act and FDA implementing regulations.

 

Sincerely,

Carrie Newcomer, PharmD
Regulatory Review Officer
Division of Drug Marketing,
Advertising, and Communications
Application Submission