Inspections, Compliance, Enforcement, and Criminal Investigations
Village Compounding Pharmacy Response Letter
HANCE SCARBOROUGH, LLP
ATTORNEYS AND COUNSELORS AT LAW
Terry L. Scarborough
Direct: (512) 487-4006
February 19, 2008
Tracking No. 8626 1516 0383
Mr. Edwin Ramos
U.S. Food and Drug Administration
4040 North Central Expressway, Suite 300
Dallas, TX 75204
Re: Warning Letter No. 2008-DAL-WL-05
Dear Mr. Ramos:
I write in response to the United States Food and Drug Administration's ("FDA"'s) January 7, 2008 "Warning Letter" issued to Phil Pylant as owner of Village Compounding Pharmacy ("Village" or the "Pharmacy") in Houston, Texas. The Warning Letter accuses Village of violating the FDCA's misbranding and "new drug" provisions.
Village is a "compounding pharmacy" as defined in Thompson v. Western States Med. Ctr., 535 U.S. 357 (2002) as well as all applicable laws of the State of Texas. Village combines, mixes, or alters ingredients to create drugs on the order of a licensed physician when no commercially-available drug is suitable for administration to a specific patient. Village is in good standing with the laws of the State of Texas, compounds only upon the order of a licensed physician, and does so only in the ordinary course of its business of compounding at retail. Among the drugs compounded by Village are non-commercially available hormone replacement therapies containing estriol.
Village is an extremely well-respected compounding pharmacy. Village was the first compounding pharmacy in Texas to receive PCAB accreditation. PCAB is a board founded by the American College of Apothecaries, American Pharmacists Association, International Academy of Compounding Pharmacists, National Association of Boards of Pharmacy, National Community Pharmacists Association, National Council of State Pharmacy Association Executives, National Home Infusion Association and the United States Pharmacopeial Convention. To earn this accreditation, Village completed an exhaustive application process; documented its written policies; provided an analysis of its quality procedures; and submitted itself to an equally exhaustive on-site inspection led by compounding experts. Village follows the guidelines of USP Chapters <<795>> and <<797>> related to sterile and non-sterile pharmaceutical compounding. Village has never been disciplined by the Texas State Board of Pharmacy, or any other authority, for any reason.
Mr. Pylant is the President and CEO of Village. He is also an expert in the field of compounding and molecular biochemistry. A highly abbreviated version of his curriculum vitae is attached as Exhibit "A". Based upon his knowledge, skill, experience, education and training, he knows that estriol is essential to the safe and efficacious creation of customized hormone replacement therapies. Without estriol, hundreds of thousands of individuals--often women suffering from the effects of menopause would needlessly suffer.
The January 7, 2007 FDA Warning Letter is the first accusation of professional misconduct Village has ever received. Village treats these accusations very seriously; however, knowing that Village openly has been compounding hormone replacement therapies that include estriol for at least thirteen years with no complaint from the FDA or the Texas State Board of Pharmacy, Village must treat the Warning Letter with skepticism. The following timeline relevant to the Warning Letter has been taken into account in evaluating Village's concerns and this response:
1. To repeat, Village has been compounding hormone replacement therapies using estriol for at least thirteen years without any complaint or disciplinary response from the FDA, the Texas State Board of Pharmacy, or any other authority.
2. In 2004, ten pharmacies filed a lawsuit in the United States District Court for the Western District of Texas, Midland-Odessa District, the Hon. Judge Robert Junell presiding. See Med. Ctr. Pharmacy v. Gonzales, 451 F. Supp. 2d 854 (W.D. Tex. 2006). The pharmacies sought a judicial declaration that compounded preparations, properly defined, are not "new drugs" within the meaning of the United States Food, Drug and Cosmetic Act ("FDCA" or the "Act").
3. In October 2005, Wyeth, a large manufacturer (as opposed to a pharmaceutical compounder) of menopause drugs, filed a Citizens Petition with the FDA seeking to have certain forms of hormone replacement therapy declared illegal under the Act.
4. On August 30, 2006, the Midland Court ruled that pharmaceutical compounding upon the order of a licensed physician does not create a "new drug" within the meaning of the FDCA, and is therefore legal under the Act.
5. The FDA subsequently appealed the Med. Ctr. Pharmacy case to the United States Court of Appeals for the Fifth Circuit. Significantly, the FDA did not file an application for, nor receive, a stay of the Court's ruling by either Judge Junell or the Fifth Circuit. Further, Wyeth filed an amicus curiae brief on behalf of the FDA in which it advocated illegalization of compounded hormone replacement therapies.
6. Oral argument in the Med. Ctr. Pharmacy appeal was scheduled for and occurred on January 10, 2008. Despite openly compounding hormone replacement therapies for years, Village received the Warning Letter dated January 7, 2008 on January 8. Subsequently, on January 9, 2008, the FDA held a closed press conference in which it announced that it was granting Wyeth's citizen petition in part and issuing Warning Letters. In other words, the FDA publicly acquiesced to Wyeth's position on compounded hormone replacement therapies literally the day before oral argument in the case that is currently dispositive of the FDA's authority to even regulate compounded preparations. It is our understanding that no qualified experts on either pharmacy compounding or estriol were permitted access to this press conference so that they could debate the FDA with even a modicum of publicity.
7. After oral argument, the FDA submitted a Fed. R. App. P. Rule 28(j) letter to the judicial panel reviewing the Med. Ctr. Pharmacy case attaching its favorable response to the Wyeth Citizens Petition and a Warning Letter similar to that received by Village, thereby injecting into that proceeding the FDA's view on the use of compounded hormone replacement therapy even though Judge Junell had determined on an undisputed record that some of the Med. Ctr. Pharmacy plaintiffs compounded hormone replacement therapies and were perfectly legal operations anyway.
8. To this date, FDA has not submitted any credible evidence that compounded hormone replacement therapy, including preparations containing estriol, is not safe and effective for use by compounding pharmacies. To the contrary, the use of estriol in compounded hormone replacement therapies is well-supported.
In sum, the January 7, 2008 Warning Letter was a proverbial "bolt out of the blue" for both Village and, presumably, the six other January 7, 2008 Warning Letter recipients, as well as the many other compounding pharmacies that compound hormone replacement therapies (particularly those containing estriol). Further, it is reasonable to conclude that this action was coordinated with the FDA's appeal of its loss in the Med. Ctr. Pharmacy case, and may even have been coordinated with its public supporter, Wyeth, in acquiescence to the pressure from that large drug manufacturer. With the foregoing in mind, it is reasonable from an objective standpoint to approach the Warning Letter received by Village with bona fide skepticism.
III. Response to Specific Claims.
A. Misbranding Under 21 U.S.C. & 321(a).
The Warning Letter begins with the assertion that Village's website contained "false and misleading" information in its advertisement of compounded hormone replacement therapies. It is from this assertion that Village must assume the FDA's position is based purely upon selective internet surveillance, and not the testing, sampling, analysis, or any other form of consultation or experience with Village or its hormone replacement therapies.1 Given the gravity of a FDA Warning Letter, Village is deeply disturbed that its reputation may be publicly tarnished without any face-to-face meeting or debate.
First, the Warning Letter accuses Village of making "unsubstantiated efficacy claims" related to its compounded hormone therapies. The FDA specifically alleges that Village's website contains advertisement that is "misleading" and/or "fails to reveal facts material in light of such representations[.]" The representations at issue are expressly stated on page 2 of the Warning Letter. There the FDA identifies advertisement of hormone replacement therapy in the successful treatment of four conditions and the effect of estrogens upon blood pressure and cognitive functions (the latter of which is qualified by the statement that such functions "may" be improved). FDA categorically states that it merely "regards" such statements as "false and misleading" simply because the FDA is "not aware of substantial evidence . . . that supports these claims." However, the Warning Letter does not disclose any evidence to the contrary-even after two years' contemplation of Wyeth's Citizens Petition. In other words, the FDA accuses Village of making false claims despite any disclosed evidence whatsoever that Village's website contained statements that were, in fact, false.
Second, the Warning letter identifies material on Village's website that "suggest[s]" that Village's compounded hormone therapy drugs are superior to other therapies, emphasizing manufactured FDA-approved drugs as the appropriate comparators. The FDA categorically states that such a suggestion is false and misleading. Although Village fully endorses the view expressed on its website, the statement at issue is not even specific to Village. In other words, FDA has a perception of a suggestion that Village specifically claims that its hormone replacement therapies are superior to all other therapies. Village is proud of its well-earned reputation, stands behind the safety and efficacy of its preparations, and knows that its preparations have assisted in the alleviation of suffering in thousands of people; however, that does not excuse FDA from ascribing to Village claims it did not make in both a Warning Letter and an attendant press conference.
Third, the Warning Letter takes issue with the term "bio-identical." The FDA states that the term "implies that [Village's] compounded hormone therapy drugs are natural, or identical to the hormones made by the body" in light of the FDA's lack of awareness of substantial evidence to support such a claim. (emphasis supplied.) According to information received from the International Academy of Compounding Pharmacists ("IACP"):
FDA-approved labeling for Prometrium ® (Progesterone, USP) Capsules states that the synthesized progesterone in this drug is "chemically identical to progesterone of human ovarian origin." Solvay, the manufacturer of this product, notes on its website that Prometrium ® is "Bio-identical to the progesterone that is naturally produced by your own body." www.prometrium.com (last visited Jan 29, 2008). Ascend Therapeutics similarly claims on its website for EstroGel® (estradiol gel) that EstroGel is "bio-identical estrogen replacement therapy that comes from a plant source ... the estrogen in EstroGel is similar to the one your body produces naturally." www.estrogel.com (last visited Jan 29, 2008).
See King, L.D., IACP Response to FDA Actions Against BHRT (Feb. 5, 2008). Village is unaware of any reason for the FDA to ignore such claims when made by drug manufacturers while simultaneously explaining to Village, a compounding pharmacy, that such claims are unsupported by "substantial evidence," unless there is a legally significant difference between manufacturers and compounding pharmacies-a position the FDA has publicly rejected.
At the soul of the FDA's Warning Letter is an inappropriate shifting of the burden of proof from the FDA to Village to demonstrate "through adequate and well controlled clinical investigations" that its website statements are not "false and misleading" as that phrase is used by the FDA.2 The FDA clearly knows that compounded preparations, properly defined, are incapable of undergoing the multi-million dollar "investigations" required to satisfy the FDA because compounded preparations are prescription- and patient-specific. Further, the FDA clearly knows as a losing party and current appellant in the Med. Ctr. Pharmacy case that FDA authority to regulate compounding pharmacy at all has already been rejected. Even if the FDA will ultimately be held to have regulatory authority over compounded hormone replacement therapy, all that is known or knowable to Village is that the only provision of 21 U.S.C. § 352 (under which the FDA accuses Village of misconduct) even mentioning compounds is § 352(o), which applies only to drug manufacturers disguised as compounding pharmacies. Given the foregoing, the tenor, accusations and timing of the FDA's Warning Letter and attendant press conference are premature and unduly aggressive, if not wholly inappropriate.
Despite all the foregoing, and contrary to Village's solid judgment, Village has elected to voluntarily suspend the internet statements with which the FDA takes issue. This voluntary suspension is not in any way a concession that the allegations contained in the FDA's Warning Letter have merit. Copies of the pertinent Village website pages, before and after receipt of the Warning Letter, are attached hereto as Exhibits "B" and "C." Further confirmation may be obtained by visiting Village's website at http://www.villagecompounding.com.
B. "New Drug" Claims.
Village has never before been accused of creating a "new drug" under the FDCA. Compounded preparations are not "new drugs" under 21 U.S.C. § 321(p) as alleged in the Warning Letter. While claiming that there is "substantial authority" to the contrary, the FDA is well aware that the only case mentioned in the Warning Letter directly addressing whether compounded preparations are "new drugs" is the Med. Ctr. Pharmacy case, which held that they are not.
It is insufficient for the FDA to issue a Warning Letter against Village, based on distinguishable authorities cited in the Warning Letter, while ignoring the only authority directly on-point. The FDA is the losing party to a case currently on appeal which says the FDA is flat-out wrong. A federal judge has spoken. The FDA is acting outside its authority and essentially is flaunting the judicial branch of the United States government.3
Instead, the FDA directs Village to FDA Compliance Policy Guide ("CPG") section 460.200 for an enumeration of non-exclusive "factors" that the FDA "considers" in deciding to initiate enforcement actions against compounding pharmacies.4 CPG 460.200 was cited by Judge Junell as one of several bases for holding that compounded preparations are not "new drugs" within the meaning of the FDCA because the CPG emphasizes that the FDCA applies to drug manufacturers, not compounding pharmacies:
The language in CPG 460.200 demonstrates that the FDA draws a line between compounding for an individual patient pursuant to a prescription from a licensed practitioner and compounding that rises to the level of manufacturing. The Court finds this distinction further supports the exemption of compounded drugs from the new drug definitions, if the drugs are created for an individual patient on the basis of a prescription from a licensed practitioner.
Med. Ctr. Pharmacy, 451 F. Supp. 2d at 864. Despite this inconsistency, the FDA continues to state that Village may not compound hormone replacement therapy containing estriol because estriol is not a component of an FDA-approved drug and Village has not obtained an FDA-sanctioned investigational new drug application. The FDA apparently asserts that compounded drugs-which are created because no FDA-approved drug is available-must be compounded from an active pharmaceutical ingredient contained in an FDA-approved drug. Village questions how and to what extent a compounding pharmacy could reasonably comply with such a mandate and retain its status as a compounding pharmacy, since, by definition, it cannot and will not create analogs of commercially-available FDA-approved drugs. Nor do Village's compounded preparations require an investigational new drug application. They are incapable of, and not intended to be, ultimate FDA-approved drugs.
Village categorically rejects the FDA's accusation that it is compounding "new drugs." The FDA is currently on the losing end of this debate and, until a court of final authority holds otherwise, Village will not concede that its compounded preparations are "new drugs" under the Act.
C. Misbranding Regarding Estriol.
The FDA concludes by stating that Village's compounded preparations containing estriol are misbranded and do not bear adequate directions for their use. Village is unaware of any actual FDA inspection or analysis of Village's preparations5 and cautions the FDA that if it acquired such preparations, it did so surreptitiously without Village's knowledge that the FDA did not have the required prescription from a duly licensed physician to receive such preparations.
Estriol is an estrogen produced in significant quantities only in the placenta of pregnant women. In comparison to other hormones, estriol is relatively weak. However, among other functions, it acts to partially block receptors in the human system which might otherwise be overwhelmed by administration of the other, more potent estrogens. Use of estriol in any drug whether manufactured or compounded-self-evidently reduces the risks associated with hyper-dosage of other estrogens that might inflame the risk of diseases such as breast cancer in high-risk women seeking hormone replacement therapy to reduce the symptoms of menopause.
Again, Village has been informed by IACP as follows:
Estriol has been approved and marketed for more than 40 years in Europe and Asia for the treatment of post-menopausal symptoms. Such drugs include, for example, Organon's Ovestin and Janssen's Ortho-Gynest. Even Wyeth, which urged FDA to act against estriol-containing BHRT products on grounds that "their sale without prior FDA approval . . . violates the new drug provisions of the Act and poses a serious threat to public health" markets two estriol-containing menopause drugs in Germany called Cyclo-Menorette ® and Estriolsable ®.
(King, L.D., supra) (emphasis in original) (internal citations omitted). The IACP letter further reminds the FDA that estriol has been used to treat menopause and other estrogen-deficiency related conditions since at least 1940-two years after passage of the Act. Id. The bottom line is that everyone knows estriol is an essential component of any scientifically credible compounded hormone replacement therapy practice. If a hormone-replacement pharmacist cannot use estriol, he or she cannot operate professionally. The FDA's categorical "prove it" belies motives that should be incomprehensible to the entire pharmaceutical industry, whether manufactured or compounded, unless those motives are unassociated with health and the palliation of suffering.
Moreover, the United States Pharmacopoeia includes an estriol monograph. The USP has set standards for drugs for well over a century. The USP establishes official standards for drugs and also establishes official standards for new drugs based upon drug company data. Once standards are developed by the USP, then the FDA enforces them. Federal drug-regulation legislation has encouraged or mandated compliance with USP standards for decades. As a PCAB-accredited pharmacy, Village only compounds preparations in conformance with the USP. The FDA's sudden about-face on the use of estriol does not comport with the FDCA's history, language, mission or intent.
Village categorically rejects the FDA's assertion that its compounded preparations containing estriol violate the Act in any way. Further, assuming arguendo that the FDA is ultimately held to have the authority to regulate estriol under the FDCA, the Warning Letter issued against Village was deliberately timed to influence a pending court case-a virtual admission that the FDA knows, at a minimum, that the law it cites has been rejected once and is in flux. This constitutes premature and selective prosecution against Village, which Village challenges.
IV. Request for Publication.
Village requests that this Response be posted on the FDA website.
The January 7, 2008 Warning Letter issued by the FDA to Village Compounding Pharmacy is objectionable, motivationally questionable, and factually and legally incorrect. But, since Village is much smaller than FDA's manufacturers, it has voluntarily elected to suspend the internet statements complained of in an effort to secure peace. Otherwise, Village categorically rejects the FDA's position with respect to those statements, as well as the FDA's position on compounded hormone replacement therapy generally, or compounds made using estriol specifically.
Terry L. Scarborough
Cc: Mr. Phil Pylant
1 To Village, FDA's actions suggest that the FDA either (1) does not wish to discuss this matter with Village; (2) does not have the expertise to discuss this matter with Village; or (3) simply does not care in light of other FDA priorities.
2 While tangential to this Warning Letter response letter, Village questions whether the FDA has the authority to regulate Village's website statements pursuant to the United States Supreme Court's ruling approving the advertisement of compounded preparations in Thompson v. Western States Med. Ctr., 535 U.S. 357 (2002).
3 The fact that the Med. Ctr. Pharmacy case is on appeal is of no moment, as the government failed to secure a stay of judgment in either the trial or appellate courts. It is bound.
4 Apparently, the FDA entertains additional factors unknown and unknowable to compounding pharmacies.
5 The Warning Letter discloses none.
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