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  1. Warning Letters


Kirkman Laboratories, Inc.

Kirkman Laboratories, Inc.

United States


United States



1850 M STREET, N.W., SUITE 800
WASHINGTON, D.C. 20036-5819
TELEPHONE (202) 223-5120
FACSIMILE (202) 223-5619

February 3, 2016

Maria P. Kelly-Doggett
Compliance Officer
Seattle District
U.S. Food and Drug Administration
22215 26th Avenue SE, Suite 210
Bothell, WA 98021

Steve Tave, Acting Director
Kathy Anderson, Deputy Director
Office of Unapproved Drugs and Labeling Compliance
Center for Drug Evaluation and Research
Food and Drug Administration
HFD-310, Room 5182
White Oak Office Building 51
10903 New Hampshire Avenue
Silver Spring, MD 20993

Drug Shortages Staff

RE: Warning Letter SEA 16-07 Issued to Kirkman Laboratories, Inc.

Dear Ms. Kelly-Doggett, Mr. Tave and Ms. Anderson:

We write on behalf of the Kirkman Group and Kirkman Laboratories Inc. (Kirkman) in response to the U.S. Food and Drug Administration Seattle District’s January 13, 2016 warning letter issued to Kirkman (Attachment 1).

Kirkman has manufactured and distributed sodium fluoride as a prescription drug since 1949. Kirkman’s sodium fluoride products serve a medically important, unmet need and have been generally recognized as safe and effective for decades. We respectfully request a meeting or conference call with the District Compliance Office and the Office of Unapproved Drugs and Labeling Compliance to discuss the significant impact that singling out Kirkman fluoride prescription drug products for enforcement action will unfairly have on Kirkman and why such action against Kirkman and all those who market such products would have a serious impact on the national effort to address the well-established public health issue of childhood dental decay.

I.    Background on Importance of Fluoride Supplementation With Prescription Drug Products

Childhood tooth decay is a significant public health concern. As the U.S. Preventive Services Task Force (USPSTF) stated in its Final Recommendation Statement, Dental Caries in Children from Birth Through Age Five Years: Screening, May 2014 (Attachment 2), “[e]arly childhood caries can cause pain, loss of teeth, caries later in life, impaired growth/weight gain, missed school days, and negative effects on quality of life. Caries in early childhood are associated with failure to thrive and can affect speech, appearance, and school performance.” May 2014 USPSTF Recommendation.

Additionally, as USPSTF has noted, the 1999-2004 National Health and Nutrition Examination Survey (NHANES) demonstrated that this issue has widespread impact. “Approximately 42% of children ages 2 to 11 years have dental caries in their primary teeth. After decreasing from the early 1970s to the mid-1990s, the prevalence of dental caries in children has been increasing, particularly in young children ages 2 to 5 years.” Id (citing Dye BA, Tan S, Smith V, Lewis BG, Barker LK, Thornton-Evans G, et al. Trends in oral health status: United States, 1988–1994 and 1999–2004. Vital Health Stat 11. 2007;(248):1-92).

Accordingly, USPSTF “recommends that primary care clinicians prescribe oral fluoride supplementation starting at age 6 months for children whose water supply is deficient in fluoride.” This is a “B” recommendation, which means that USPSTF “recommends the service. There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.” USPSTF Grade Recommendations after July 2012 (Attachment 3).

The American Dental Association and American Academy of Pediatrics also recommend fluoride supplementation where there is inadequate water fluoridation. “When access to community water fluoridation is limited, fluoride can be supplemented in liquid, tablet, or lozenge form.” See American Academy of Pediatrics Recommendations (Attachment 4) and ADA, Fluoride Supplements (Attachment 5). Fluoride supplements require a prescription. A 2010 American Dental Association (ADA) evidence-based clinical guideline recommends fluoride supplements be prescribed only to children determined to be at high risk for the development of caries whose community water source is suboptimal. See 2010 ADA Guideline (Attachment 6).

The scientific literature demonstrates that fluoride supplementation works. Among the six studies assessing the effectiveness of fluoride supplementation, USPSTF found that all six supported the conclusion that supplementation decreases the rate of dental caries in children five and younger who live in areas with inadequate water fluoridation. “Relative reductions ranged from 52% to 72% for decayed, missing, and filled teeth and from 51% to 81% for decayed, missing, and filled tooth surfaces. Across all six trials, relative reductions with fluoride supplementation ranged from 32% to 72% for decayed, missing, and filled teeth and from 38% to 81% for decayed, missing, and filled tooth surfaces versus placebo (vitamin drops) or no supplementation.” USPSTF Recommendation. Accordingly, removing Kirkman’s fluoridation products from the market would remove a crucial tool in this country’s fight against dental caries.

Removing Kirkman’s fluoridation products from the market would also undermine the policies of the Patient Protection and Affordable Care Act (ACA)1. Under the ACA and its implementing regulations, group health plan and health insurers are required to cover “evidence-based items or services that have in effect a rating of “A” or “B” in the current recommendations of the United States Preventive Services Task Force,” without any cost-sharing requirements such as copays or deductibles. 42 U.S.C. 300gg-13(a); 45 C.F.R. § 147.130. Targeted enforcement activity against prescription fluoridation products would render the USPSTF’s B recommendation for fluoride meaningless and would severely curtail access to the very products that USPSTF has identified as beneficial. In addition, under the ACA, the Social Security Act continues to exclude fluoride preparations from the list of drugs that states may exclude or otherwise restrict from Medicaid coverage. See 42 U.S.C. § 1396r-8(d)(2)(E).

II.    FDA’s Unapproved Drug Enforcement Program

All sodium fluoride prescription drugs for oral administration are subject to the September 11, 2011 “Guidance for FDA Staff and Industry, Marketed Unapproved Drugs – Compliance Policy Guide, Sec. 440.100 Marketed New Drugs Without Approved NDAs or ANDAs” (CPG). That guidance explains that a product is not “considered a new drug if it is generally recognized as safe and effective (GRAS/GRAE) and has been used to a material extent and for a material time.” See CPG at 12 (citing 21 U.S.C. § 321(p)(1) and (2)). Kirkman has marketed its sodium fluoride prescription drug products since the 1940s as part of the national and international effort against pediatric dental caries.

Additionally, taking enforcement action against sodium fluoride prescription drug products that have worked safely and effectively for decades is plainly inconsistent with the enforcement priorities and principles outlined in FDA’s CPG. FDA has indicated that its first priority is to remove those products that are unsafe and then those that are ineffective. FDA has also said that it will take action against fraudulent drugs, drugs that present a direct challenge to the new drug approval and OTC drug monograph systems, unapproved new drugs that are violative of the FFDCA in other ways and drugs that have been reformulated to evade an FDA enforcement action. Compliance Guide at 4-5.

Kirkman’s sodium fluoride prescription drug products fit none of these enforcement criteria. Kirkman’s sodium fluoride prescription drug products are safe and effective and have been so for decades. Kirkman is not aware that there are pending new drug applications for sodium fluoride prescription drug products and there likely will be no applications given the narrow use of these products. Thus, the continued presence of Kirkman’s products on the market should not be expected to undermine the drug approval system.

Kirkman’s sodium fluoride prescription drug products also do not represent a direct challenge to the OTC drug monograph system. Indeed they are complementary and provide a product that addresses the 6 months to 3 year old age group, a group not covered by the OTC monograph at 21 C.F.R. § 355, Anticaries Drug Products for OTC Use.

Additionally, after Kirkman discussed its sodium fluoride prescription drug products with the then Acting District Director and her colleagues in November 2013, it committed to engage a consultant to evaluate its manufacturing of sodium fluoride drug products for compliance with 21 C.F.R. Part 211. Kirkman engaged a consultant and, at considerable expense, established a separate facility to manufacture and package these sodium fluoride prescription drug products. That facility was inspected by FDA in 2015 and the company believes that it has addressed all observations noted at the close of the inspection and that its manufacturing facility is cGMP compliant.

Finally, we note that FDA’s historical approach has been to take action against all prescription drug products of a class marketed without an approved application. See Compliance Actions by Drug Class, available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/SelectedEnforcementActionsonUnapprovedDrugs/ucm238675.htm#oxysingle. To Kirkman’s knowledge, FDA has not sent warning letters to any of the other sources of fluoride supplements. These include Sancilio, http://sancilioproducts.com/brands-products/generic-products/dental-health-2/, against whom Kirkman filed a complaint with FDA in 2014 that their products are unlawful, and Medical Products Laboratories, http://www.mplusa.com/, which is a supplier to and competitor of Kirkman. There is no reason that Kirkman should face targeted enforcement activity that is not also applied to the other manufacturers of sodium fluoride prescription drug products, given its long history of safe and responsible marketing.

Kirkman sodium fluoride prescription drug products are an important tool in the fight against childhood dental decay. We would therefore welcome the opportunity to discuss the issues raised in this letter with you in greater detail.

Sincerely yours,
Anthony L. Young
Peter R. Mathers 


David K. Humphrey
Chief Executive Officer and President
Kirkman Laboratories, Inc.
1 42 U.S.C. § 18001 et seq.

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