Wyeth Citizen Petition
Sarah E. Botha
October 6,2005 202.719.7411
sbotha@wrf.com
BY HAND DELIVERY
Division of Dockets Management
Food and Drug Administration
Department of Health and Human Services
5630 Fishers Lane, Room 1061 (HFA-305)
Rockville, MD 20852
Re:
Submission of Citizen Petition on Behalf of Wyeth
1 Dear Sir or Madam:
Please accept for filing the attached citizen petition submitted on behalf of Wyeth in
four copies pursuant to 21 C.F.R. $9 10.20, 10.30.
Sincerely,
Sarah E. Botha
cc:
Steven K. Galson, Acting Director, Center for Drug Evaluation and
Research
David J. Horowitz, Director, Office of Compliance
Jane A. Axelrad, Director, Office of Regulatory Policy
Sheldon T. Bradshaw, Chief Counsel, Office of the Chief Counsel
Steven D. Silverman, Director, Division of New Drugs and Labeling
Compliance
Thomas W. Abrams, Director, Division of Drug Marketing, Advertising, and
Communications
1776 K STREET NW
INASHINGTON, DC 20006
PHONE 202 719 7000
:AX 202.719.7049
‘ilrglnla otfice
7925JONES BRANCH DRIVE
';UITE 6,!00
IMcLEAN. VA 22102
PHONE 703.905.2800
IAX 7113 905 2820
www.wrf.con-i
Andrew S. Krulwich
October 6,2005
202.719.7003
akrulwic@wrf.com
Division of Dockets Management
Food and Drug Administration
Department of Health and Human Services
5630 Fishers Lane, Room 1061 (HFA-305)
Rockville, MD 20852
Re: Citizen Petition Seeking FDA Actions to Counter Flagrant Violations of the
Law by Pharmacies Compounding Bio-Identical Hormone Replacement
Therapy Drugs that EndanPer Public Health
Dear Sir or Madam:
Pursuant to 21 C.F.R. $3 10.20, 10.30, the undersigned, on behalf of Wyeth,
submit this petition under sections 501, 502, and 505 of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. $5 351, 352, and 355) (“FDCA or “the Act”) to request the
Commissioner of Food and Drugs to take the actions specified below to address
issues related to the growing, unlawful manufacture and marketing of so-called
“bio-identical hormone replacement therapies” (“BHRT”),’ which are available
from numerous compounding pharmacies throughout the United States. It is
important to note that this petition is not directed in any way at those pharmacies
which satisfy legitimate patient needs by compounding individual products for
individual needs that cannot be met by an FDA-approved product.
Wyeth is a leading manufacturer of FDA-approved estrogen-containing
hormone therapy (“HT”) drug products and is a leader in women’s health. As such,
Wyeth feels compelled to advise FDA of the following activities and the potential
’ The term “bio-identical hormone replacement therapies” is used throughout this petition to
refer to the unapproved hormone therapy products at issue because this is the term used
within the compounding industry to describe the products. Although Wyeth has no
knowledge of the specific ingredients that are actually being utilized in the preparation of
these products, the compounding pharmacies represent that the products differ in
composition from FDA-approved hormone therapies, such as Wyeth’s approved,
conjugated estrogen hormone therapies.
October 6,2005
Page 2
risks to which American women may be exposed due to insufficient information
BHRT compounding pharmacies provide on the risks that accompany their
products. Many of these pharmacies fail to inform consumers even of those risks
that FDA requires be included in the labeling of estrogen-containing drug-products.2
Specifically, FDA has indicated that in the absence of comparable data, the risks of
all estrogens should be assumed to be similar.3 However, even though BHRT
products contain estrogen, we are not aware that adequate and well-controlled
clinical trials have been conducted that provide substantial evidence of the products’
safety and efficacy, as required by the FDCA and FDA’s regulations.4
During the past few years, the market for BHRT products has grown,
spurred by publicity from such notable personalities as Suzanne Somers. By
misrepresenting the reports of risks associated with d estrogen-containing hormone
therapies and capitalizing on the publicity of “bio-identical” alternatives,
compounding pharmacies have created a niche commercial market for BHRT drug
products. The compounding pharmacies investigated that distribute these products
have veered far away from traditional compounding activities; rather, they
manufacture and market these products not as drugs compounded to address
particularized patient needs in limited circumstances, but as safer and more effective
wholesale substitutes for FDA-approved drug products for any woman wanting
hormone therapy. And, they do this with misleading labeling and advertising
* See 21 C.F.R. fj 310.515.
3 FDA, Guidance for Industry, Labeling Guidance for Noncontraceptive Estrogen Drug
Products for the Treatment of Vasomotor Symptoms and Vulvar and Vaginal Atrophy
Symptoms -Prescribing Information for Health Care Providers and Patient Labeling
(draft) at 2 (Feb. 2004) (“Draft Estrogen Labeling Guidance”).
’ 21 U.S.C. 3 355(b)(l) and(d); 21 C.F.R. 0 314.126.
October 6,2005
Page 3
without the required evidence to substantiate their claims. See Metcalf Pharmacy
website, http://www.metcalfpharmacy.cor&rhrt.htm (Ex. A).
In short, these compounding pharmacies are engaging in the manufacture,
sale, distribution and promotion of prescription drugs without complying with the
requirements set forth in the FDCA and FDA’s applicable regulations. Specifically,
the pharmacies are manufacturing and marketing the drugs without the required
FDA approval in violation of section 505; the products are also misbranded and
adulterated under sections 501 and 502 of the Act. 21 U.S.C. $4 351,352 and 355.
The public interest requires that this activity, which is putting women’s health and
safety at risk, be stopped.
I.
Action Requested
The undersigned, on behalf of Wyeth, respectfully request the
Commissioner of Food and Drugs to take the following actions with regard to
pharmacies engaged in the compounding of so-called “bio-identical hormone
replacement therapy” drugs:
A.
Enforcement Actions
Initiate enforcement actions, in the form of seizures, injunctions and/or
warning letters, against any BHRT compounding pharmacies whose
facilities or whose manufacturing, labeling, advertising or dispensing
practices FDA determines are in violation of the FDCA.
B.
Labeling and Advertising Disclosures
1.
Commence investigations to determine whether entities involved
either in dispensing BHRT products or in promoting such products to
patients or to health care professionals are providing proper patient
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October 6,2005
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package inserts for those drugs with each package that is intended to
be dispensed to a patient, pursuant to 21 C.F.R. $ 3 10.5 15, and are
including material facts and risk information in all labeling and
advertisements provided to patients and to health care professionals
or directed to the consumer population at large, including the
following:
(4 That the BHRT product is a new drug and does not have FDA
approval;
04 That the BHRT product is/was compounded, or “prepared,”
in a pharmacy that is not required to comply with FDA
current good manufacturing requirements;
cc> That the BHRT product has not been demonstrated to be safe
or effective for any use, or safer or more effective than FDA-
approved HT products.
2.
Require that all labeling and advertisements, whether directed to
physicians or to patients and consumers, explain these material facts
and all risk information, and require that consumer-directed materials
be written in language that will be easily comprehensible to
laypersons and that all comparative or superiority claims be
appropriately supported by legitimate and sufficient data.
3.
Require, for those BHRT pharmacies that have failed to provide
these material facts and/or risk information in labeling and in
advertisements, that the pharmacies take the following actions:
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October 6, 2005
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(a> Where the pharmacy has failed to provide the aforementioned
material facts and/or risk information in labeling or
advertisements provided to health care professionals, FDA
should require the pharmacy to notify each health care
professional who submitted a prescription for a BHRT drug
during the previous twelve months that the information was
not provided; and
(b) Where the pharmacy has failed to provide the aforementioned
material facts and/or risk information in labeling or
advertisements provided to patients or other potential
consumers, FDA should require the pharmacy to post a
correction at the pharmacy counter as well as provide
individual notice to each patient to whom BHRT drugs were
dispensed during the previous twelve months that the
information was not provided.
C. FDA Alert or Talk Paper
Issue an Alert or Talk Paper directed to consumers, health care providers and
the compounding industry that:
1.
Advises pharmacies of their obligations under the Act and FDA
regulations when compounding, dispensing, and promoting so-called
“bio-identical hormone replacement therapy” drugs.
2.
Notifies consumers, health care providers, and pharmacies that FDA
has neither approved compounded BHRT products as safe and
effective, nor determined that they are safer or more effective than
FDA-approved HT products.
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October 6,2005
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3.
States that there are inherent risks in such products and describe the
risks, with particular reference to the Agency’s 1977 regulation
requiring patient package inserts for non-contraceptive estrogen
products and the 2004 Draft Estrogen Labeling Guidance, as well as
the boxed warning and other risk information deemed necessary by
the Agency following the reports of the Women’s Health Initiative
(“WHY) study.
4.
Forcefully reminds health care professionals and pharmacies that
BHRT drugs can be compounded lawfully only to meet the
individualized needs of individual patients that cannot be met by
FDA-approved hormone therapies and cannot be marketed or
advertised without including all material facts and risk information.
5.
Confirms that:
(
4
Any labeling or advertising contrary to these principles is
false, misleading and unlawful;
C-
4
Any compounding or distribution of BHRT drugs beyond
traditional compounding practices as described in the FDA’s
Compliance Policy Guide for pharmacy compounding
(“CPG”) is also unlawful; and
>
Any such unlawful promotion or compounding will subject
the BHRT products and pharmacies involved to seizure and
injunction.
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II. Statement of Grounds
A. Background
1. Estrogen-Containing Hormone Therapies
Estrogen and combination estrogen/progestin prescription drug therapies are
widely used for the treatment of post-menopausal symptoms in women. Wyeth is
the manufacturer of the FDA-approved HT drugs PremproB (conjugated
estrogens/medroxyprogesterone acetate tablets) and PremphaseB (conjugated
estrogens/medroxyprogesterone acetate tablets) (containing estrogens with a
progestin), and PremarinB (conjugated estrogens tablets, USP) (containing
estrogens only).
FDA has mandated patient labeling for all non-contraceptive prescription
estrogens since 1977, in an effort to ensure safe and effective use of the drugs. The
Agency determined that patients must be advised of the risks of endometrial cancer
and other adverse health effects that are associated with the products so that patients
can properly assess the advantages and risks of taking them. See Requirement for
Labeling Directed to the Patient, 42 Fed. Reg. 37636, 37637 (July 22, 1977)
(codified at 21 C.F.R. 4 3 10.515) (Ex. B). Prompting the requirement was FDA’s
express concern that physicians might not otherwise adequately provide their
patients with full information on the risks and benefits of these drugs, and that
patients might forget or misinterpret any information that was provided. Id.
More recently, the National Institute for Health supported a study as part of
the Women’s Health Initiative (“WHY’) that was designed to evaluate the long-term
benefits and risks of estrogen or combination HT products in post-menopausal
women. The study received a huge amount of publicity in the lay press, leaving
many women with questions and concerns. To warn and alert physicians and
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October 6,2005
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patients to these findings and their implications for women’s health, FDA stated that
all HT products should add a boxed warning as well as updated relevant
information. Wyeth’s Prempro@, Premphase@ and Premarin@ HT products, among
others, have updated, FDA-approved labeling incorporating both the boxed warning
and the information from the WHI studies. As discussed below, labeling of BHRT
products usually does not incorporate either the boxed warning or other important
risk. information -a failing that sparks serious safety concerns.
2.
“Compounded” Bio-Identical Hormone Replacement
Therapy Drugs
Pharmacies have traditionally engaged in drug compounding to provide
variations of commercially-marketed drugs in order to accommodate the particular
medical needs of specific individuals. For example, upon receipt of a valid
prescription from a licensed practitioner, a pharmacist might prepare an FDA-
approved prescription drug in a different dosage form or without a particular
ingredient in response to the needs of an individually identified patient.
In the wake of the WHI findings, women with concerns about HT have
become targets for vendors offering unproven alternatives as a false remedy. In that
regard, many pharmacies are manufacturing and marketing “bio-identical” hormone
therapies, which they are promoting as risk-free alternatives to FDA-approved HT
products, under the false guise of “compounding.” The pharmacies use the terms
“bio-identical” and “natural” to describe their products because they utilize
hormones purporting to have the same molecular structure as those present in
humans. In reality, though, these products are plant derived (see handouts on bio-
identical hormones, provided by Mary M. Morton, FNP-C (Ex. C)) and further
processed to resemble human hormones; they are not “natural” to humans.
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October 6,2005
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Moreover, rather than compounding to meet the specific individualized
needs of a particular person, these pharmacies are capitalizing on the confusion
raised by the WHI study by falsely trumpeting their own “bio-identical” products to
all women as a no-risk alternative to FDA-approved HT products, some even going
so far as to provide CME programs that misrepresent the safety profiles of both
FDA-approved HT and BHRT. See Brochure for Health Max Pharmacy Regional
Symposium on Bio-Identical Hormone Replacement Therapy (N.Y., Apr. 30,2005)
(Ex. D). This practice goes far beyond traditional compounding: the pharmacies are
selling and marketing their products as wholesale substitutes for the FDA-approved
hormones for use by all women.
Thus, “bio-identical” HT products are being dispensed to thousands of
patients across the county without adequate data to demonstrate safety or efficacy,
not merely to a few patients to meet their individual needs which cannot be met by
FDA-approved therapies.’ The “compounded” BHRT products contain estrogen
ingredients to which specific risks have been attributed by FDA and the WHI study,
but patients using these products receive little or no information about the potential
risks of these drugs. In addition, some of the products being advertised contain an
active ingredient (Estriol) that is not a component of any FDA-approved drug,
raising additional public health and safety concerns for any women taking these
products. Intensifying this problem is the fact that some compounding pharmacies
substitute compounded BHRT products when filling prescriptions for prescribed
5 Some of the pharmacies at issue encourage patients to submit a saliva sample for hormone
testing, claiming that the BHRT product may then be tailored to the individual needs of the
patient. Saliva cannot, however, be used to accurately measure an individual’s hormone
levels, as the hormones in saliva fluctuate considerably during the course of a single day.
Instead, hormone levels may only be accurately measured by drawing a blood sample. The
use of this inaccurate measure in formulating the compounded drug is an added risk related
to these pharmacies’ sale of BHRT products.
October 6,2005
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FDA-approved HT products, creating potential medical concerns, liability issues for
doctors and manufacturers, and a threat to the integrity of FDA’s whole system of
drug approval. See Scarbrough Medical Arts Pharmacy’s “Dear Doctor” letter (Ex.
E). In a sense, these pharmacies are improperly treating compounded BHRT
products as though they were approved, generic equivalents of FDA-approved
hormone products -but this is not the case.
The BHRT “compounding” industry is growing rapidly in light of media
attention and promotion through talk shows and publications such as Suzanne
Somers’ books, The Sexy Years and Slim and Sexy Forever, as well as advertising in
the lay press and on numerous websites. See, e.g. Women’s Health America,
http://www.womenshealth.com (last visited Oct. 5, 2005). Under FDA’s standards,
these pharmacies are clearly “manufacturing” rather than engaging in traditional
compounding to meet individualized needs. They are taking advantage of the lack
of information about these products to offer them in a way that presents potentially
serious health risks to a large patient population. FDA’s response to this abuse and
threat to public health must be visible and far-reaching.
Labeling and advertising materials distributed by the following
compounding pharmacies in association with their BHRT drugs provide additional
examples of the unlawful conduct in which a great many BHRT compounding
pharmacies are engaged:
l Silverbow Rx Compounding Phapromotional materials in Ex. F).
rmacy, Butte, Montana. (See
l PenCol Medisave Pharmacy, Denmaterials in Ex. G).
ver, Colorado. (See promotional
l The Medicine Shoppe, Bountiful,
H).
Utah. (See “Dear Doctor” letter in Ex.
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October 6,2005
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l
Ranch0 Park Compounding Pharmacy, Los Angeles, California. (See
promotional materials in Ex. I).
l
Red River Pharmacy Services, Texarkana, Texas. (See “Dear Doctor”
letters in Ex. J).
l
Women’s Health America/Madison Pharmacy Associates, Madison,
Wisconsin. (See promotional materials in Ex. K).
Pharmacies such as these are acting as manufacturers based on their practices of
compounding drugs using bulk active ingredients that are not components of FDA-
approved drugs, promoting BHRT products as wholesale substitutes for FDA-
approved hormones, making comparative safety and efficacy claims without
substantiation meeting FDA requirements, and compounding drug products that are
essentially copies of FDA-approved drugs. In addition, these labeling and
advertising materials being distributed in association with BHRT drugs violate
FDCA requirements and render the products misbranded.
However, these pharmacies are just a sampling; many other pharmacies
across the country compounding BHRT products are engaging in similar practices
that exceed traditional, legitimate compounding activities and pose substantial risks
to public health and safety.
B.
FDA’s Legal Authority over Compounded Pharmaceuticals and
the Pharmacies Engaged in Compounding
1. FDA Authoritv to Regulate Compounded Drugs
Retail pharmacies that engage in drug compounding are generally subject to
the new drug, adulteration, and misbranding provisions of the FDCA. See, e.g., In
re Wedgewood T/ill. Pharmacy, Inc., 270 F. Supp. 2d 525, 543-44 (D.N.J. 2003)
(holding that the FDCA provisions regarding new drugs, misbranding and
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October 6,2005
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adulteration are applicable to the relevant pharmacy practices), aff’d on other
grounds, 421 F.3d 263 (3d Cir. 200Q6 FDA has long recognized that compounded
drugs typically cannot meet the Act’s new drug application (“ND,“) pre-market
approval requirements because they are made in such small amounts, based on the
needs of individual patients, that testing for safety and efficacy would not be
feasible. Due to this fact and to the legitimate benefits compounded drugs can
provide to individual patients with conditions or individualized variations of
conditions that cannot be treated with FDA-approved drugs, FDA has exercised its
discretion to refrain from enforcing these requirements with respect to pharmacies
engaged in legitimate compounding to meet the individualized needs of these
patients.
However, at the same time, FDA has also recognized the public health issues
that can arise when pharmacies compound drugs in a manner resembling
manufacturing. Therefore, the Agency’s enforcement discretion has been
contingent on a pharmacy limiting its compounding to only those practices that are
recognized as traditional compounding activities. FDA has advised the industry of
specific types of activities that it will consider to be illegal drug manufacturing, as
’ Retail pharmacies that compound drug products are exempt only from the registration
requirements of the FDCA and from certain inspection provisions of the Act, provided they
comply with local laws regulating the practice of pharmacy. See 21 U.S.C. 0 360(g)(l); 21
U.S.C. 5 374(a)(2). H owever, compliance with local laws does not exempt compounding
pharmacies from any other provisions of the FDCA. If FDA determines that a pharmacy’s
practices fall outside of traditional compounding activities, the pharmacy will be subject to
all the registration and inspection provisions, as well as the other provisions applicable to
prescription drugs. See FDA, Compliance Policy Guides Manual, Section 460.200
Pharmacy Compounding at 4 (posted June 7,2002) (the “2002 CPG” or “current CPG”),
http://www.fda.gov/OHRMS/DOCKETS/98fr/02D-0242~gdl0001 .pdf (explaining that such
pharmacies will be subject to misbranding actions under 21 U.S.C. 5 352(o), which renders
drugs misbranded if they are manufactured, prepared, propagated, compounded, or
processed in an establishment not duly registered under 21 U.S.C. 0 360).
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October 6,2005
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/ opposed to permissible drug compounding, in a Compliance Policy Guide (“CPG”)
for pharmacy compounding.7 The current CPG was issued in June 2002,
subsequent to the Supreme Court’s decision in Thompson v. Western States Medical
Center.’ The guidance lists factors the Agency considers in determining whether a
pharmacy’s compounding activities constitute drug manufacturing, thereby
prompting the need for regulatory action.’ These include:
l
“Compounding finished drugs from bulk active ingredients that are not
components of FDA approved drugs without an FDA sanctioned
investigational new drug application;”
0
“Compounding drug products that are commercially available in the
marketplace or that are essentially copies of commercially available,
FDA-approved drug products;”
a
“Compounding [ ] drugs in anticipation of receiving prescriptions,
except in very limited quantities in relation to the amounts of drugs
compounded after receiving valid prescriptions;”
’ The original CPG, issued in 1992, was prompted by concern over the manufacture and
distribution of “commercial amounts” of unapproved new drug products by pharmacies,
which often lacked “adequate recordkeeping” practices to trace and recall harmful products,
or lacked “proper labeling or adequate manufacturing controls to assure the drugs’ quality.”
See Press Release, FDA, Compliance Policy Guide Addresses Prescription Drug
Compounding (Apr. 14, 1992) http://www.fda.gov/bbs/topics/ANSWERS/ANSOO394.html.
8 Thompson v. Western States Med. Ctr., 535 U.S. 357 (2002).
9In Western States, the Supreme Court held that the mere act of advertising or engaging in
promotional activities could not establish that a pharmacy was operating as a manufacturer.
Id. at 376-77. As a result, FDA omitted from the 2002 CPG the act of soliciting
compounding of specific drugs or classes of drugs, which had been included in the 1992
CPG as an action indicative of manufacturing activity. However, as discussed inj?a at n.
22, the Western States opinion and other First Amendment precedent make clear that FDA
can regulate advertising for compounded prescription drugs to prevent false and misleading
advertisements.
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October 6,2005
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0
“Compounding drugs for third parties who resell to individual patients or
offering compounded drug products at wholesale to other state licensed
persons or commercial entities for resale;” and
0
“Using commercial scale manufacturing or testing equipment for
compounding drug products.”
1 2002 CPG at 3-4.
Using these factors, among others, if FDA determines that compounding
pharmacies are engaged in the manufacture and distribution of unapproved new
drugs in a manner that is “clearly outside the bounds of traditional pharmacy
practice,” FDA will treat those pharmacies as manufacturers and require compliance
with the new drug, adulteration and misbranding provisions of the Act. Id. at 3.
2.
FDA’s
Pharmacies
Since issuing the 2002 CPG, FDA has uncovered numerous instances of
compounding pharmacies engaging in unauthorized manufacturing activities. FDA
has sent warning letters to compounding pharmacies in the following
circumstances: lo
l
Pharmacies were using active ingredients in their compounded products
that were not components of any FDA-approved drug product (See, e.g.,
Warning Letter No. 2004-DAL-WL-16 to Peoples Pharmacy, Inc. (June
7,2004); Warning Letter No. 04-NWJ-14 to Drugs Are Us, Inc. DBA
Hopewell Pharmacy (June 7,2004); Warning Letter No. FLA-04-34 to
Axium Healthcare Pharmacy (June 7,2004); Warning Letter No. DEN-
05-08 to Palace Pharmacy (Mar. 23,2005));
l
There was no evidence of particular patients having a medical need for
specific variation between a commercially-available drug and the
pharmacy’s compounded drug product (See, e.g., Warning Letter No.
lo FDA warning letters can be found generally at http://www.fda.gov/foi/warning.htm.
October 6,2005
CIN-04-4746 to Gentere, Inc. DBA Teregen Labs (July 13,2004);
Warning Letter No. NWE-1 S-03 W to Carneys Drug (May 27,2003);
Warning Letter No. 2004-NOL-36 to Delta Pharma, Inc. (Sept. 17,
2004));
Pharmacies were making products that were essentially copies of
commercially-available products (See, e.g., Warning Letter No. UN-04-
4746; Warning Letter No. FLA-04-34; Warning Letter No. NWE-1%
03W; Warning Letter No. 2004-NOL-36; Warning Letter No. SJN-05-02
to Respi Care Group (Dec. 20,2004); Warning Letter No. 2005-NOL-06
to Lincare, Inc., and Reliant Pharmacy Services, Inc. (Dec. 9,2004));
Pharmacies were selling compounded products without a prescription or
manufacturing them in anticipation of receiving a prescription (See, e.g.,
Warning Letter No. CIN-04-4746; Warning Letter No. 2004-NOL-36;
Warning Letter No. 2004-DT-03 to White Lake Pharmacy (Jan. 16,
2004); Warning Letter No. CBER-04-003 to Custom Compounding
Centers (Dec. 23,2003); Warning Letter No. 3003528540 to Med-Mart
Pulmonary Services (Sept. 30,2002));
Pharmacies were making and distributing products in large quantities,
including drugs for general sale as “office stock” to physicians and
clinics (See, e.g., Warning Letter No. CIN-04-4746; Warning Letter No.
3003528540; Warning Letter No. SJN-05-02; Warning Letter No. 2005-
NOL-06; Warning Letter No. 2004-NOL-36);
Pharmacies were manufacturing products in such large quantities that
use of commercial scale equipment was required (See, e.g., Warning
Letter No. 3003528540);
Pharmacies were furnishing products to prescribers as samples (See, e.g.,
Warning Letter No. 3003528540).
In each of these instances, FDA stated that engaging in such practices
subjects compounding pharmacies and the products they produce to the new drug,
adulteration, and misbranding provisions of the FDCA. FDA has advised these
pharmacies that their actions are in violation of the Act unless they (1) submit
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October 6, 2005
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NDAs or ANDAs; (2) ensure that their products bear adequate directions for use
and, in some cases, adequate warnings against use by children; and (3) ensure that
their products are manufactured in a duly registered establishment and in
accordance with current good manufacturing practices regulations.”
To our knowledge, FDA has not yet initiated enforcement action against any
BHRT compounding pharmacy. It is past time for the agency to do so.
C.
Factual, Legal and Policy Bases for FDA to Initiate Enforcement
and Regulatory Action
1.
Many Pharmacies Compounding Bio-Identical Hormone
Replacement Therapy Drugs Are Engaged in Unlawful
Manufacturing Under FDA’s CPG
Based on the examples provided with this petition, it is clear that numerous
compounding pharmacies are exposing women to potential health risks by engaging
in the manufacture of BHRT products in violation of the FDCA. As discussed
below, these pharmacies are using unapproved ingredients to compound their
products and are promoting their own BHRT formulations as wholesale substitutes
for FDA-approved estrogen-containing hormone therapies. These pharmacies
undoubtedly engage in additional as yet undetermined practices indicative of
manufacturing activities rather than legitimate compounding under FDA’s CPG.
By manufacturing prescription drug products without meeting the approval,
labeling and manufacturing requirements of the FDCA and FDA regulations, BHRT
” FDA generally based these warnings letters on inspections of purported compounding
pharmacies that the Agency reasonably suspected of engaging in manufacturing activities in
violation of the FDCA. FDA’s authority to inspect a pharmacy in order to determine
whether it is acting as a drug manufacturer has been upheld in court. See In re Wedgewood
Vill. Pharmacy, Inc., 270 F. Supp. 2d 525,551-52 (D.N.J. 2003), aff’d, 421 F.3d 263,273-
74 (3d Cir. 2005).
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October 6,2005
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compounding pharmacies are introducing drug products into the market that have
not been tested appropriately for safety and efficacy, lack appropriate labeling
information and have been manufactured under conditions that do not meet current
good manufacturing practices (“cGMPs”). This problem is exacerbated by the fact
that the products contain estrogens, drugs for which FDA requires that particular
labeling and warnings be provided directly to patients. Thus, important public
health interests and the law combine to strongly impel FDA to initiate regulatory
action against BHRT compounding pharmacies that are failing to comply with the
new drug, adulteration, and misbranding provisions of the FDCA and to prevent
further violations.
a.
Pharmacies Using Unapproved Bulk Active
Ingredients Are Engaged in Manufacture of Drug
Products and Their Compounded BHRT Products are
Unapproved New Drugs
FDA has expressly stated that a pharmacy is not operating as a traditional
compounding pharmacy if its products are compounded from bulk active
ingredients that are not components of FDA-approved drugs. 2002 CPG at 4.
Pharmacies that use unapproved ingredients in compounding drug products are
deemed to be acting as manufacturers in violation of the FDCA. As evidenced by
the attached materials, BHRT compounding pharmacies are manufacturing,
promoting and dispensing products that contain the hormone Estriol, which is not a
component of any FDA-approved drug.12 By using the unapproved ingredient
I2 See, e.g., Silverbow Rx Compounding Pharmacy’s promotional materials Bio-Identical
Hormones: Customized Replacement Therapy to Meet the Needs of Each Woman & Man
(Ex. F); PenCol Medisave Pharmacy promotional materials Beginning or Conversion to
Bio-Identical Hormone Replacement Therapy (BHRT) (Ex. G); The Medicine Shoppe’s
Oct. 10,2001, “Dear Doctor” letter (Ex. H); Ranch0 Park Compounding Pharmacy’s
promotional materials Bio-Identical Hormone Replacement Therapy for Women (Ex. I);
Red River Pharmacy Services’ “Dear Doctor” letter (Ex. J); Women’s Health
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October 6,2005
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Estriol in their “compounded” BHRT products, BHRT compounding pharmacies
are engaging in manufacturing new, unapproved drug products rather than in
traditional compounding activities.
The use of Estriol in compounded BHRT drugs parallels the activities of pharmacies that recently received FDA warning letters based on their practice of
compounding finished drugs from the bulk active ingredient domperidone, which is also not a component of any FDA-approved drug. See, e.g., Warning Letter No. FLA-04-34; Warning Letter No. 04-NWJ-14; Warning Letter No. 2004-DAL-WL- 16; Warning Letter No. DEN-05-O. FDA stated that compounded products
containing the unapproved substance domperidone are “drugs” under section
201 (g). See, e.g., Warning Letter No. FLA-04-34, at 2. FDA further noted that
because domperidone is “not generally recognized by qualified experts as safe and
effective for [its] labeled use, the products are new drugs, as defined by section
20 1 (p) of the Act.” Id. The introduction of these products into interstate commerce
without a new drug application violated section 505(a) and the failure of the
products to bear adequate directions for use rendered the products misbranded under
section 502(f)( 1). Id.
FDA’s position regarding the use of the unapproved ingredient Estriol in
compounded BHRT products can be no different. FDA should therefore initiate
enforcement action against compounded BHRT products containing Estriol and the
pharmacies manufacturing them on the grounds that the products are adulterated and
(Continued . . .)
America,/Madison Pharmacy Associates website,
http://www.womenshealth.com/estrogen-therapy.html(Ex. K).
WievRein &Fielding LLP
October 6,2005
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misbranded and that their sale without prior FDA approval of an NDA violates the new drug provisions of the Act and poses a serious threat to public health.
b.
Promotional Claims Made by BHRT Compounding
Pharmacies Demonstrate That They Are Engaged in
Manufacturing Activities
The attached materials are examples of common unlawful practices by
BHRT compounding pharmacies that promote compounded BHRT products as wholesale substitutes for FDA-approved hormones, urge doctors to rely on BHRT as an alternative method of treatment and make comparative claims regarding the safety and effectiveness of “bio-identical” and synthetic hormones. l3
By marketing their products as wholesale substitutes for FDA-approved HT products, it is apparent that BHRT compounding pharmacies intend their BHRT drugs to be competitive products in the market rather than traditional compounded drugs, which are substitutes for approved drugs in limited cases based on an individual patient’s particular medical circumstance. For example, one pharmacy
I3 See PenCoI Medisave Pharmacy, supra (offering to help patients “make the conversion to
bio-identical from synthetic hormones” and promoting the “benefits of BHRT” over
synthetic products) (Ex. G); The Medicine Shoppe’s Oct. 10,200 1, “Dear Doctor” letter
(advising doctors to consider “switch[ing]” their patients currently on products like
Premarin@ and Prempro@ to BHRT products, due to a purported shortage of animal-
derived conjugated estrogen needed to produce the commercial products) (Ex. H); Ranch0
Park Compounding Pharmacy, supra (stating that data from the “large studies on HRT” are
not applicable to BHRT products, and comparing the risks of non-bio-identical hormones to
the benefits of BHRT products) (Ex. I); Red River Pharmacy Services’ “Dear Doctor” letter
(promoting the use of BHRT products “as an alternative to synthetic hormone replacement
therapy” in light of the WHI study findings) (Ex. J); Women’s Health America,/Madison
Pharmacy Associates Website, http://www.womensheaIth.com/hrtregimen.html (comparing
FDA-approved progestin products, termed “synthetic,” with compounded “natural”
progesterone products), http://www.womenshealth.com/library/hrt_conf..html (discussing
“downside” of synthetic hormones and the “natural alternative” of compounded hormone
products) (Ex. K).
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October 6,2005
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boasts “over 5,000 patients,” whom it claims are “correctly and safely using these
products with few side effects, alleviating uncomfortable symptoms, and decreasing
the potential long-term risks that come along with synthetic hormone replacement.”
PenCol Medisave Pharmacy, supra (Ex. G). These and similar claims establish that
such compounded BHRT products are new drugs; the compounding pharmacists are
therefore manufacturers seeking to market to an uniformed patient population and
are subject to the new drug, adulteration and misbranding provisions of the FDCA.
See 21 U.S.C. 5 321(g)(l)(B)-(C); 21 C.F.R 5 201.128.
C.
The Compounded BHRT Products That Pharmacies
Are Producing Are Copies of Commercially-
Available Drugs and Therefore Production of Those
Products Constitutes Manufacturing
Under FDA’s 2002 CPG, compounding of products that are “essentially
copies of commercially available FDA-approved drug products” is an indicator that
a pharmacy is engaged in manufacturing activities rather than traditional
compounding in violation of the Act. 2002 CPG at 4. The legislative history of the
1997 FDAMA amendments to the FDCA indicates that a compound should be
considered a “copy” if, among other things, the product does not “produce a
‘significant difference’ for the particular patient” that uses it. H.R Conf. Rep. No.
105-399, at 94 (1997), as reprinted in, 1997 U.S.C.C.A.N. 2880,2884 (Ex. L).
However, while a “significant difference” can result where an ingredient that would
have a particular health effect is removed or substituted, it cannot occur in situations
“where it is readily apparent, based on the circumstances, the ‘significant
difference’ is a mere pretext to allow compounding of products that are essentially
copies of commercially available products.” Id.
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October 6,2005
Page 2 1
Pursuant to this policy, FDA has issued warning letters to pharmacies <
engaged in such practices. See, e.g., Warning Letter No. ClN-04-4746 at 2 (noting
pharmacy’s products were “copies,” because the pharmacy could not “document a
medical need for particular patients for these versions of otherwise commercially-
available products”); Warning Letter No. NWE- 18-03 W at 2 (pharmacy was
“copying a commercially-available drug” by producing the product in different
strengths without being able to document a medical need for particular patients for
particular variations); Warning Letter No. SIN-05-02 at 2 (use of a different dosage
form did not create a “meaningful distinction,” especially absent a documented,
“patient-specific, medical need for the compounded product”); Warning Letter No.
2005-NOL-06 at 2 (pharmacy’s offering of the products in a different dosage form
did not produce a “meaningful distinction” from the commercially-available
product).
Here, FDA has already expressly recognized that “natural” hormone
therapies have the same risk profile as commercially-available hormone products.14
Thus, the change from manufactured hormone ingredients to “natural” ingredients
via “compounding” does not create a significant difference for a patient using the
BHRT products. In addition, many BHRT pharmacies are not compounding
variations of FDA-approved hormone products based on the specific medical needs
of particular patients. For these reasons, BHRT pharmacies are compounding <
copies of FDA-approved hormone products, and their practices constitute
manufacturing under the 2002 CPG.
* *
I4 See discussion in& Parts II.C.2.a.ii-iii.
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October 6,2005
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In sum, many BHRT pharmacies are engaged in drug manufacturing rather
than traditional compounding. As a result, there is no basis for FDA to continue to
exercise its enforcement discretion to exempt these pharmacies from all the relevant
requirements of the FDCA, including the adulteration and misbranding provisions,
and the requirement to obtain approved NDAs prior to marketing these drug
products. Rather, because of the serious public health interests implicated by these
activities, the Agency should act promptly, forcefully and comprehensively to end
these practices.
2.
BHRT Compounding Pharmacies Are Violating FDCA
Requirements for the Labeling and Promotion of Drugs
a.
BHRT Pharmacies Are Violating the Labeling
Requirements of the FDCA and FDA Regulations
Numerous BHRT compounding pharmacies are distributing brochures,
letters to doctors, and other literature that constitute labeling subject to section 502
of the Act.” See, e.g., Exs. H (Medicine Shoppe’s Oct. lo,2001 “Dear Doctor”
letter) and J (Red River Pharmacy Services ’ “Dear Doctor” letter). Others are
distributing such messages via the Internet. See, e.g., Ex. K (Women’s Health
America/Madison Pharmacy Associates Website, http://www.womenshealth.com).
As discussed below, in addition to never having been approved by FDA, much of
this labeling fails to meet the minimum statutory and regulatory requirements for
drug labeling. l6
” Labeling is defined as “all labels and other written, printed, or graphic matter upon any
article or any of its containers or wrappers or accompanying such article.” 2 1 U.S.C. 3
321(m). Labeling includes brochures, booklets, mailing pieces, detailing pieces, bulletins
and letters. 21 C.F.R. 9202.1(l)(2).
I6 Many of the other materials attached to this petition as examples, including the pamphlets
and other literature that describe the products to a consumer-audience, are also labeling to
YViiev Rein & Fielding LLP
October 6,2005
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i.
BHRT Pharmacies’ Labeling Materials
Violate FDA’s Regulations on their Face and
Render the Products Misbranded
Under the FDCA, a drug is misbranded unless its labeling bears adequate
directions for use. 21 U.S.C. 8 352(f)(l). As permitted by the FDCA, FDA
regulations provide an exemption for prescription drugs from the adequate
directions for use requirement, but only if certain conditions are met. 21 C.F.R. 5
20 1.100. One of these conditions is that labeling for the prescription drug must bear
the following information:
[aIdequate information for such use, including
indications, effects, dosages, routes, methods, and
frequency and duration of administration and any
relevant warnings, hazards, contraindications, side
effects, and precautions, under which practitioners
licensed by law to administer the drug can use the
drug safely and for the purpose for which it is
intended, including all conditions for which it is
advertised or represented.
21 C.F.R. 0 201.1 OO(d)( 1). This requirement applies to “any labeling . . . whether
or not it is on or within a package from which the drug is to be dispensed,
distributed by or on behalf of the manufacturer, packer, or distributor of the drug,
that furnishes or purports to furnish information for use or which prescribes,
recommends, or suggests a dosage for the use of the drug.” Id. tj 201.100(d).
(Continued . . .)
the extent the compounding pharmacies distribute these materials in the pharmacy, with the
dispensed products, or directly to physicians and other medical practitioners by detailers.
Any promotional materials that are distributed completely separately from the BHRT
products constitute “advertising” under the FDCA and FDA regulations. Because it is
unclear into which category some of the materials at issue would fall, the petition addresses
both the FDCA labeling and advertising violations that are evident in the promotional
materials at issue.
W&y Rein &Fielding UP
October 6,2005
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None of the BHRT pharmacies’ promotional labeling Wyeth has collected
provides the information required by section 201.100(d); it is unlikely that many, if
any, BHRT compounding pharmacies provide this information on their BHRT
product labeling, depriving users of information about proper use and risks that
FDA deems vital. Accordingly, BHRT drug products marketed and sold using
labeling that lacks this important information -i.e., virtually all BHRT products -
are not exempt from FDA’s adequate directions for use requirements, and are
therefore misbranded.
ii.
BHRT Pharmacies’ Labeling Materials are
also Misleading Under the Act, Rendering the
Products Misbranded
Retail pharmacies that dispense prescription drugs are not exempt from the
FDCA prohibition on false and misleading labeling.17 In determining whether a
drug is misbranded as a result of misleading labeling, FDA considers
not only representations made or suggested by
statement, word, design, device, or any combination
thereof, but also the extent to which the labeling . . .
fails to reveal facts material in the light of such
representations or material with respect to
consequences which may result from the use of the
article to which the labeling . . . relates under the
conditions of use prescribed in the labeling . . . thereof
or under such conditions of use as are customary or
usual.
I7 See 21 U.S.C. 3 352(a); Phurm. Mfis. Ass ‘~1v. FDA, 484 F. Supp. 1179, 1184-86 (D. Del.
1980), af’dper curium, 634 F.2d 106, 108 (3d Cir. 1980) (noting that section 503(b)(2)
exempts dispensed prescription drugs from the labeling requirements of sections 502(b),
relating to quantity of contents, 502(e), relating to common names, and 502(f), relating to
“adequate directions for use,” but explicitly does not exempt prescriptions drugs from the
requirement of section 502(a) that their labels not be misleading).
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October 6,2005
Page 25
~ 21 U.S.C. 0 321(n) (emphasis added).
Many of the representations and omissions in the BHRT compounding
pharmacy materials are misleading under this standard. For example, as discussed
further below, many BHRT compounding pharmacies’ promotional materials
contain safety and efficacy claims, both explicit and implied, but contain no
information on the side effects or contraindications of the BHRT products they
promote. See, e.g., PenCol Medisave Pharmacy pamphlet (Ex. G), Silverbow Rx
Compounding Pharmacy pamphlet (Ex. F), and Ranch0 Park Compounding
Pharmacy brochure (Ex. I).” The omission of such material information renders
these materials misleading under 21 U.S.C. 6 321(n). As a result, the products
being promoted are misbranded.
Moreover, clinical data on “bio-identical hormone replacement therapies”
are insufficient to support express and implied claims of either safety, efficacy or
superiority that are often contained in promotional materials for BHRT products.
Specifically,
l
We are unaware of any well-controlled clinical investigations meeting
FDA’s standards demonstrating efficacy and safety of any BHRT
product(s).
l
We are unaware of data meeting FDA’s standard for superiority claims -
i.e., well-controlled, head-to-head clinical studies comparing any BHRT
product(s) with FDA-approved HT products - that demonstrate
superiority or even comparable efficacy (see 21 C.F.R.
$0 202.1 (e)(4)(ii)(B), 202.1 (e)(6)(i)-(ii)).
l
FDA’s recent Guidance to the industry regarding labeling requirements
for noncontraceptive estrogen drug products confirms that “there is no
‘* See inj-a Part II.C.2.b.ii.
October 6,2005
Page 26
evidence that the use of ‘natural’ estrogens results in a different
endometrial risk profile than synthetic estrogens at equivalent estrogen
doses.” Draft Estrogen Labeling Guidance at 2.
l
In a fact-sheet for consumers on hormone therapy, FDA states that “at
this time, we do not know if herbs or other ‘natural’ products are helpful
or safe. Studies are being done to learn about the benefits and risks.”
FDA, Menopause & Hormones (Fact Sheet) (July 2003, available at
http://www.fda.gov/womens/menopause/mht-FS.html (emphasis added).
Thus, the compounding pharmacies’ claims that their “bio-identical”
hormone products are safe and effective -or that they have superior safety profiles
to FDA-approved HT products -lack clinical support. Under FDA’s own Guidance
and Fact Sheet, such claims are false and misleading. Significantly, at least one
pharmacy has even admitted that little clinical testing has been conducted for these
products, even though that pharmacy makes express safety and efficacy claims for
its products in its promotional pamphlet. See Ex. F. Because FDA has determined
that there is no evidence that “natural” hormones contain fewer potential risks than
other hormone products, and promotional materials distributed by BHRT
pharmacies cite no studies establishing that the products being promoted are safe
and effective, claims of safety and efficacy for BHRT compounded products -
superiority, comparative, or otherwise -lack adequate substantiation. Such
unsubstantiated claims mislead users about the safety and efficacy of these products,
creating a serious public health concern and violating the Act. See United States v.
Sevre XEZeemosynary Corp., 479 F. Supp. 970,980 (S.D. Fla. 1979) (determining
that promotional literature distributed regarding a compounded product was
misleading “labeling” due to the lack of clinical proof, in the form of adequately
controlled clinical studies, that the compounded products were effective for any
indicated use). As a result, the BHRT drugs promoted using such claims are
misbranded.
Wiley
Rein & FieldingLLP
October 6,2005
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. . .
111.
Any Failure by BHRT Pharmacies to
Distribute Patient Package Inserts with their
Compounded Drug Products Violates the Act
and Renders the Products Misbranded
FDA regulations obligate all pharmacies to distribute patient package inserts
(“PPI’s”) when dispensing prescription estrogen products. 21 C.F.R.
5 3 10.515(b)(l); Requirement for Labeling Directed to the Patient, 42 Fed. Reg. at
37638 (Ex. B) (stating that in the overwhelming majority of cases the pharmacist
will dispense the patient labeling along with the drug).” This requirement applies
to pharmacies that dispense compounded drug products containing estrogens
because the regulation covers “drug products containing estrogens” and is not
limited to synthetic estrogens, conjugated estrogens or FDA-approved estrogen
products. 21 C.F.R. 0 301.515(a). As a result, any BHRT pharmacy that is not
including the required PPIs with its compounded estrogen products is dispensing
misbranded products under section 502(a) of the Act. 21 C.F.R. 0 310.515.
In furtherance of these requirements, FDA’s recent Draft Estrogen Labeling
Guidance sets forth in detail the information PPIs should include to comply with the
regulation. See Draft Estrogen Labeling Guidance. Among the information that
must be presented in the PPI is a statement of the benefits and proper uses of
estrogens, as well as a description of the contraindications, most serious risks and
other side effects related to estrogen use. The Draft Guidance explicitly confirms
that drugs produced from “natural” estrogens are subject to the same labeling
requirements as FDA-approved hormone products. Specifically, the Draft Guidance
I9 Indeed, in upholding the PPI requirement as a valid exercise of FDA’s authority under the
FDCA, one court acknowledged that “physicians us well us pharmacists are required to
provide the labeling when they act as dispensers of the medication.” Pharm. M@s. Ass ‘n,
484 F. Supp. at 118 1 (emphasis added).
Wiley Rein & F’iel&g LLP
October 6,2005
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provides that labeling for health care providers include a statement that no evidence
exists indicating that the use of “natural” estrogens “results in a different
endometrial risk profile than synthetic estrogens at equivalent doses.” Id. at 2, 10.
It is highly unlikely that many BHRT compounding pharmacies provide such a
statement.
The extent to which BHRT compounding pharmacies are violating these
requirements is impossible for Wyeth to ascertain. Frankly, however, the fact that
other labeling prepared by these pharmacies fails to comply with FDA regulations
suggests strongly that many of these pharmacies are not providing PPIs and that any
PPls that are provided do not meet the requirements set forth in the FDA Draft
Guidance.
These are not minor, technical omissions. They go straight to the heart of
informing women taking estrogen products. These pharmacies’ failure to provide
this legally-required information demonstrates forcefully that they are simply trying
to dupe an unsuspecting patient population. In light of the substantial public health
concern, FDA must take prompt action to ensure that BHRT compounding
pharmacies are complying with their obligation to dispense PPIs with their
compounded products.
iv.
BHRT Promotional Materials are Misleading
Under the Compounding Pharmacy Industry’s
Own Guidelines
In addition to misleading patients in violation of FDA regulations, BHRT
promotional materials of the kind discussed above also violate the compounding
pharmacy industry’s own standards regarding appropriate content for advertising
and other promotional materials. In its Legal and Ethical Advertising of
Compounded Medications statement, the International Academy of Compounding
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October 6,2005
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Pharmacists (“IACP”)20 advises that pharmacists “should not make claims as to
safety and effectiveness of compounded medications [and should] [alvoid
statements, including performance claims that would be false or misleading.” The
IACP further advises pharmacists to “avoid referring to manufacturer’s products, or
trade names in promotional materials,” and notes:
Such references, or claims that a compounded product
is similar to a manufactured product, could be viewed
as misleading, suggesting that the compounded
product is as safe and effective as the commercially
available product. Such a drug may be considered
“misbranded” under the FD&C Act and subject to
FDA enforcement action.
IACP, Legal and Ethical Advertising of Compounded Medications,
http://www.iacprx.org/pdf/legal-and-ethical.pdf (Ex. M).
The IACP has also developed a Code of Ethics for compounding
pharmacists. The Code provides that pharmacists have a responsibility not to
“engage in marketing or promotional practices that: a) utilize manufacturers’ names
or the names of patented products; b) create misinformation with claims of
therapeutic equivalence; c) create misinformation by perception that compounded
products are generic products, and d) base such promotion and advertising solely on
price.” IACP, Code of Ethics, http://www.iacprx.org/pdf/ethics.pdf (Ex. N).
Despite these industry guidelines, many BHRT compounding pharmacies’
promotional materials not only make reference to the brand names of commercially-
available estrogen-containing hormone therapies, such as Premarin@, Provera@ and
PremproB, but also compare the safety and efficacy of the BHRT products to that of
lo The IACP describes itself as an international non-profit organization that represents and
serves over 1,300 compounding pharmacists. See http://www.iacprx.org.
Wiley Rein &Fielding UP
October 6,2005
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the commercial products. See, e.g., PenCol Medisave Pharmacy, supra (Ex. G);
Ranch0 Park Compounding Pharmacy, supra (Ex. I); Red River Pharmacy Services’
“Dear Doctor” letter (Ex. J). Moreover, as noted above, there is anecdotal evidence
that some BHRT compounding pharmacies are substituting BHRT compounded
products as equivalents for FDA-approved hormone products that have been
prescribed by doctors, thus, in effect, treating them as generics (supra, at 9-10).
In short, even the compounding pharmacy industry representatives consider
the advertising claims being made by many BHRT compounding pharmacies to be
misleading and inconsistent with the industry’s ethics, which poses a grave public
health concern and renders the products “‘misbranded’ under the FD&C Act and
subject to FDA enforcement action.” IACP, Legal and Ethical Advertising of
Compounded Medications (Ex. M).
b.
BHRT Compounding Pharmacies’ Advertising
Violates the FDCA by Improperly Omitting the Brief
Summary
The brief summary requirement in section 502(n) of the FDCA applies to
“a advertisements for any prescription drug” (21 C.F.R. $ 202.l(e)( 1) (emphasis
added)), and the responsibility for inclusion of the brief summary lies with the
manufacturer, packer, or distributor of the advertised drug who issued the
advertisement or otherwise caused the ad to be issued. 21 U.S.C. 0 352(n). No
exemption is provided to advertising for compounded prescription drugs,” and
21 Section 503(b)(2) of the FDCA does not exempt pharmacies from complying with the
brief summary requirement in advertisements that are published prior to the pharmacies’
receipt of a prescription and distribution of a compounded drug product. Instead, the
FDCA only provides an exemption from certain labeling requirements at the time a
prescribed prescription drug is dispensed. See 21 U.S.C. 353(b)(2); S. Rep. No. 82-946
(195 1), as reprinted in, 195 1 U.S.C.C.A.N. 2454,2462-63 (Ex. 0); H.R. Rep. No. 82-700,
at 16 (195 1) (Ex. P); see also United States v. ArticZes ofDrug, 625 F.2d 665, 670 (5th Cir.
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Y
October 6,2005
Page 3 1
public health would be endangered if a brief summary were not required. No basis
exists for distinguishing compounded drugs from other drugs in this regard and,
thus, failure to comply with the brief summary requirements renders the
compounded drug products being advertised misbranded. 21 U.S.C. 9 352(n).
i.
BHRT Compounding Pharmacies Must
Comply With the Brief Summary Requirement
BHRT compounding pharmacies are certainly “distributors” to whom the
brief summary requirement applies. Under FDA’s regulations, to “distribute means
to sell, offer to sell, deliver, or offer to deliver a drug to a recipient.” 21 C.F.R. Q
203.3(h). Because BHRT compounding pharmacies sell, offer to sell, deliver and
offer to deliver the compounded drug products that they dispense, they are
“distributors,” and their advertisements for compounding BHRT products must
contain a “brief summary.”
Moreover, these pharmacies are also “manufacturers” of the compounded
BHRT products they dispense for the purposes of the brief summary requirement,
even if FDA finds that a particular pharmacy’s activities do not rise to the level of
“manufacturing” under the 2002 CPG. This is because the factors considered in
determining whether an entity is a “manufacturer” under the drug marketing
(Continued . . .)
1980) (noting that “Prior to being dispensed a prescription drug must meet the misbranding
requirements of section 352 . . . . After a prescription drug has been lawfully prescribed, it is
exempt from most of the requirements of section 352 but must meet the labeling
requirements of section 353(b)(2).“). In addition, while FDA regulations provide an
exemption from the brief summary requirement for advertisements directed toward
compounding pharmacies by manufacturers of prescription drug components, this
exemption does not apply to pharmacies’ own consumer- and physician-directed
advertisements for finished compounded products. See 21 C.F.R. 5 202.l(e)(2)(iii).
Nothing in Western States exempts compounding pharmacies from the brief summary
requirement.
Wilev Rein & Fielding LLP
October 6,2005
Page 32
regulations are different from the factors considered under the 2002 CPG on
pharmacy compounding. Compare 2002 CPG with 21 C.F.R. 4 201.1(b). The
factors applicable to marketing are mixing, granulating, milling, molding,
lyophilizing, tableting, encapsulating, coating, sterilizing, and filling sterile, aerosol,
or gaseous drugs into dispensing containers. See 21 C.F.R. 0 201.1(b). BHRT
compounding pharmacies obviously engage in some or all of these activities. In
short, BHRT pharmacies are subject to the brief summary requirement with regard
to any advertisements for BHRT compounded products.22
The brief summary regulations require all advertisements and other printed
materials promoting drug products to contain a true statement of information related
to side effects, contraindications, and effectiveness of the drug. Furthermore, all
information relating to the safety and effectiveness of the drug must be fairly
balanced with information relating to the side effects and contraindications. 2 1
C.F.R. 0 202.1. As demonstrated directly below, many BHRT pharmacies’
promotional materials do not satisfy this requirement, rendering the compounded
products misbranded.
ii.
The BHRT Pharmacies Have Completely
Ignored the FDCA’s Brief Summary
Requirement
Many advertisements promoting compounded BHRT products fail to contain
any information regarding the side effects and contraindications associated with the
** As the Supreme Court noted in Western States, the First Amendment does not prohibit all
regulation of commercial speech by FDA. 533 U.S. at 367. Rather, as the Court ruled in
Virginia State Board of Pharmacy v. Virginia Citizens Consumer Council, “[u]ntruthful
speech, commercial or otherwise, has never been protected for its own sake.” 425 U.S. 748,
77 1 (1976). Thus, FDA regulation of false or misleading advertising of drug products, like
the advertising at issue here, is permissible. Id.
Wiley Rein &Fielding LLP
October 6,2005
Page 33
compounded drug products that they promote. This type of omission is a serious
violation of section 502(n) that subjects users of these products to unknowing
potential health risks that FDA cannot countenance. Compounded drug products
advertised in this manner are misbranded and subject to seizure or injunction. See
21 U.S.C. $0 352(n), 332,334.
The following are examples of BHRT promotional materials that make
explicit and implied safety and effectiveness claims, without complying with the
brief summary requirement and providing a balance of side effect and
contraindication information:
0
PenCol Medisave Pharmacy’s promotional pamphlet contains a section
entitled “Benefits of BHRT,” which promises “reduction or complete
resolution” of side effects associated with the use of FDA-approved
hormones. Ex. G. The section entitled “Bio-Identical Hormone
Replacement Therapy (BHRT)” also contains safety and effectiveness
claims, including “few side effects, alleviating uncomfortable symptoms,
and decreasing the potential long-term risks that come along with
synthetic hormone replacement.” Id. Despite making these express
safety and efficacy claims, the pamphlet contains no information on the
side effects or contraindications of the advertised BRHT products.
l
Silverbow Rx Compounding Pharmacy’s promotional pamphlet contains
effectiveness claims in the section entitled “Goals of Bio-Identical
HRT.” Ex. F. The pamphlet claims that the product will “alleviate the
symptoms caused by the natural decrease in production of estrogens by
the body [and] give the protective benefits which were originally
provided by naturally occurring hormones.” Id. Another section states
“Bio-identical hormones have been shown to be clinically effective for
the treatment of menopausal symptoms; for the treatment of
postmenopausal problems . . . ; [and] in decreasing the risk of
Alzheimer’s disease and colorectal cancer.” Id. There are other efficacy
claims throughout the pamphlet. In addition, the pamphlet discusses
claimed health risks posed by hormone treatments, implying that this
pharmacy’s compounded products do not pose similar risks and are
Wiley Rein & Fielding LLP
October 6,2005
Page 34
therefore safer. Again, however, the patient and doctor are given no side
effect or contraindication information in these advertisements.
l
Ranch0 Park Compounding Pharmacy’s promotional brochure contains a
long list of risks purported to be associated with non-bio-identical
hormones (e.g., blood clots, gallbladder disease, endometrial and breast
cancer) and a long list of benefits supposedly provided by BHRT
products (e.g., relieves menopausal symptoms, reduces risk of hip
fractures, prevents and reverses osteoporosis) like those being
compounded and promoted by this pharmacy; the brochure contains no
information alerting doctor or patient to any side effects, risks, or
contraindications associated with the BHRT products being advertised.
Ex. I.
The failure to provide a brief summary in advertising materials is a severe
violation that endangers the health and safety of women who purchase BHRT
compounded products, unaware of the potential risks, contraindications and safety
parameters of the products. FDA cannot allow this practice to continue.
3.
Failure of BHRT Pharmacies’ Manufacturing Practices to
Conform to Current FDCA Requirements for Good
Manufacturing Practices Would Render the Products
Adulterated
Although Wyeth cannot determine the precise manner in which BHRT
compounding pharmacies are producing their BHRT products, it is highly unlikely
that they are in conformance with the current good manufacturing practices required
by section .501(a)(2)(B) of the FDCA. 21 U.S.C. 0 351(a)(2)(B).23 Because many
BHRT pharmacies are engaging in manufacturing, rather than traditional
~ l3 The FDCA requires that the methods used in the manufacturing, processing, packing and
holding of a drug conform to “current good manufacturing practice to assure that [the] drug
meets the requirements of [the Act] as to safe@ and has the identitv and strength, and meets
the quality and purity characteristics, which it purports or is represented to possess.” 2 1
U.S.C. 5 351(a)(2)(B) (emphasis added).
Wilw Rein &Fielding LLP
I
October 6,2005
Page 35
compounding activities, this failure to conform to section 501(a)(2)(B) would
render the products adulterated. See 21 U.S.C. 6 351(a)(2)(B); 2002 CPG at 4.
In 2001, FDA conducted a limited survey of compounded drug products by
collecting samples that could be ordered over the Internet. See CDER Report:
Limited FDA Survey of Compounded Drug Products, at 1 (last updated Jan. 28,
2003) http://www.fda.gov/cder/pharmcomp/survey.htm. FDA collected 37
products made by 12 compounding pharmacies, and conducted tests on 29 of these
products, which included compounded hormonal products. Id. Of the products
tested, 34% (10 out of 29) “failed one or more standard quality tests,” and “nine out
of the 10 products with failing analytical results failed . . . potency testing” as well
(i.e., they were subpotent). Id. at 3. In contrast, “[tlhe analytical testing failure rate
for commercially-produced drug samples has been less than 2%” since 1996, and
FDA remarked that the failure rate for the compounded products tested was “higher
than expected.” Id. at 5. While this survey was limited, FDA acknowledged that
the results “provided valuable, preliminary information on the quality of selected
compounded drug products currently marketed.” Id.
These results confirm that many compounded BHRT products would likely
fail standard quality tests, and perhaps potency testing. This evidence of non-
compliance with cGMPs should not be ignored, especially considering the
substantial public health interests at stake and the current concerns relating to the
WHI study findings which have made this patient population a target of
unscrupulous businesses. FDA should take prompt action to end this serious
violation of the Act.
Wiley Rein &Fielding LLP
October 6,2005
Page 36
III. Environmental Impact
As provided in 21 C.F.R. 8 25.30, the petitioners believe this petition
qualifies for a categorical exclusion from the requirement to submit an
environmental assessment or environmental impact statement. To the petitioners’
knowledge, no extraordinary circumstances exist.
IV. Economic Impact
As provided in 21 C.F.R. $ 10.30(b), the petitioners will submit economic
impact information upon request of the Commissioner.
V. Certification
The undersigned certify, that, to the best knowledge and belief of the
undersigned, this petition includes all information and views on which the petition
relies, and that it includes representative data and information known to the
I petitioners which are unfavorable to the petition.
Respectfully submitted,
Andrew S. Krulwich
Benjamin B. Reed
Sarah E. Botha
WILEY REIN & FIELDING LLP
1776 K Street, N.W.
Washington, D.C. 20006
Telephone 202.7 19.7000
Facsimile 202.719.7027
Counsel to Wyeth
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