Department of Health and Human Services
|Public Health Service
Food and Drug Administration
|Rockville, MD 20857|
DELIVERY SIGNATURE REQUESTED
August 18 2009
Jerry S. Roth, President
Hill Dermaceuticals, Inc.
2650 Mellonville Avenue
Sanford, Florida 32773-9311
Dear Mr. Roth:
On September 15-18,22,23, and 29,2008, the United States Food and Drug Administration (FDA) conducted an inspection of your pharmaceutical manufacturing facility, located at 2650 Mellonville Avenue, Sanford, Florida. The investigators found that your firm is marketing a misbranded drug in violation of sections 301(a), 502 (a), (f)(1) and (o), and 510(j))(2)(D) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. §§ 331(a), 352(f)(1) and (o), and 360(j)(2)(D)], and 21 CFR §§ 207.30(a)(4) and 314.70.
Unapproved and Misbranded Prescription Drugs
Based on the information collected during the inspection, you manufacture the prescription drug Tri-Luma Cream (fluocinolone acetonide 0.01 %; hydroquinone 4%; tretinoin 0.05%), under NDA 21-112. The Tri-Luma Cream ("Tri-Luma") labeling submitted during the inspection indicates that it was revised in December 2003. According to FDA records, the most recent approval date for Tri-Luma, NDC 0299-5950-30, is January 2002. We have no approved supplements for this product. Thus, the current labeling of your Tri-Luma product has not been approved by FDA.
Your marketing of Tri-Luma with a label not approved by the agency misbrands it under section 502(f)(1) of the Act, [21 U.S.C. § 352(f)(1)], which requires that all drugs have adequate directions for use, unless exempt from this requirement. Under the regulations, adequate direction for use means directions that enable a layperson to safely use the drug for its intended uses. See 21 CFR § 201.5. Tri-Luma fails to bear adequate directions for its use because the product is a prescription drug within the meaning of section 503(b)(1) of the Act, [21 U.S.C. § 353(b)(1)], and as such it is not safe for use except under the supervision of a practitioner licensed by law to administer such drug. Because the Tri-Luma product does not bear the approved labeling, it is not exempt under 21 CFR § 201.100(c)(2) from this requirement for adequate directions for use. Tri-Luma is therefore misbranded under section 502(f)(1) of the Act.
The FDA is extremely concerned about your dissemination of an unapproved PI for Tri-Luma Cream. There are numerous alarming differences between the FDA-approved PI (dated January 18, 2002) and the unapproved PI that is being disseminated by you, as summarized below:
- The unapproved PI suggests that Tri-Luma Cream is indicated for long term, repeated, or maintenance treatment of melasma. Specifically, the unapproved PI states in the Indications and Usage section that Tri-Luma is indicated for "intermittent" treatment "with cumulative treatment time of 180 days" and that "patients can be re-treated with TRI-LUMA® until melasma is resolved." However, according to the approved PI, Tri-Luma is indicated for short-term use (up to 8 weeks) only, and is "NOT indicated for the maintenance treatment of melasma." The approved PI also indicates that remission periods appear to shorten between progressive courses of treatment.
- The unapproved PI suggests that Tri-Luma Cream is safe for long term (52 week) use. Specifically, the unapproved PI presents data from uncontrolled, long term (52 week) safety studies that have not been reviewed or substantiated by the FDA. In addition, the unapproved PI claims that the long-term safety study was performed to demonstrate the local and systemic safety of Tri-Luma; however, no measures of "systemic" effects are reported in this unapproved PI. According to the approved PI, adverse events were monitored in controlled-clinical trials during an 8 week treatment period and for 6 months in an open-label long-term safety. Furthermore, long-term use may result in significant worsening of adverse events, particularly those associated with long-term use of fluorinated steroids, such as skin atrophy, steroid induced rosacea, telangiectasia and systemic absorption leading to adrenal suppression.
- The unapproved PI seriously minimizes the risks of Tri-Luma by omitting some of the documented side effects of Tri-Luma and by downplaying the severity and frequency of risks reflected in the approved PI. For example, the unapproved PI includes language in the WARNINGS section that downplays the prevalence of sulfite sensitivity in the general population and that does not appear in the approved PI. It also reports a higher number of healthy babies born from women who inadvertently used Tri-Luma during pregnancy than the approved PI, and omits the risks of dryness and pruritis at the site of application contained in parts of the approved PI's ADVERSE REACTIONS section. In addition, the unapproved PI contains assurances of safety about long-term use, stating that there was no significant increase in severity or incidence of the adverse events from long term use of Tri-Luma compared with events reported during the 8-week controlled clinical studies, and that the rate of erythema, desquamation, and burning at the site of application was actually "markedly lower" upon long-term use compared to the short-term study. As noted above, the drug is only approved for short-term use, and long-term use may result in significant worsening of adverse events.
- The unapproved label overstates the efficacy of Tri-Luma Cream by including unsubstantiated clinical study results that make Tri-Luma appear more efficacious than has been demonstrated by substantial evidence. For example, the unapproved PI reports a higher percentage of patients achieving treatment success at 8 weeks and after longer courses of therapy than the approved PI and, unlike the approved PI, it fails to mention that remission periods shorten upon repeated use of Tri-Luma.
Thus, your dissemination of this unapproved PI raises significant public health concerns. By overstating the safety of Tri-Luma and minimizing the risks associated with the use of the product, you are suggesting that Tri-Luma is safer than demonstrated. Furthermore, you suggest that Tri-Luma is useful in a broader range of conditions and is more effective than has been demonstrated by substantial evidence. Therefore, your labeling is misleading. Accordingly, because you never submitted and obtained an approved supplement for these changes, as required by 21 CFR § 314.70, Tri-Luma is misbranded under section 502(a) of the Act.
You are also in violation of the drug registration and listing requirements because you have not updated your listing by submitting the December 2003 Tri-Luma labeling, as required by Section 510(j)(2)(D) of the Act [21 U.S.C. § 360(j)(2)(D)]. Your facility is not exempt from the drug listing requirements in section 510(g) of the Act [21 U.S.C. § 360(g)]. See also 21 CFR 207.30(a)(4).
The issue and violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence or the occurrence of other violations. It is your responsibility to conduct a comprehensive audit of your facility and operations and assure compliance with all requirements of the Act and FDA regulations. Federal agencies are advised of the issuance of all warning letters about drugs so they may take this information into account when considering the award of contracts.
You should take prompt action to correct all the violations noted in this letter, and you should establish procedures whereby such violations do not recur. Failure to promptly correct violations may result in regulatory action without further notice, such as seizure and/or injunction.
Additionally, FDA may withhold approval of requests for export certificates, or approval of pending new drug applications listing your facility as a manufacturer until the above violations are corrected. A re-inspection may be necessary. If you no longer manufacture or market any of your drug products, your response should so indicate, including the reasons for, and the date on which you ceased production.
You should notify this office in writing, within fifteen (15) working days from your receipt of this letter, of the specific steps you have taken to correct the noted violations, including an explanation of each step taken to prevent recurrence of similar violations. You should include in your response documentation or other useful information to assist us in evaluating your corrections. If you cannot complete all corrections before you respond, you must explain the reason for your delay and state when you will correct any remaining deviations.
You can find guidance and information for the regulated industry regarding regulations for drug products through links at FDA's website at http://www.fda.gov/oc/industry/.
Your reply should be directed to the U.S. Food and Drug Administration, Attention: Astrid Lopez-Goldberg, Regulatory Counsel, 10903 New Hampshire Avenue, Building 51, Silver Spring, MD 20993-0002. If you have questions regarding any issue in this letter, please contact Ms. Lopez-Goldberg at (301) 796-3485.
Division of New Drugs & Labeling Compliance
Office of Compliance
Center for Drug Evaluation and Research
This page was posted on January 31, 2010.