Legal Prophylaxis Healthy Aging, May/June William J. Stilling, RPh, MS, JD

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1 Legal Prophylaxis Healthy Aging, May/June 2008 William J. Stilling, RPh, MS, JD Author s Note: This article is intended to provide education. It is not intended to establish an attorney-client relationship. Readers should not rely on this article as legal advice, but should obtain legal counsel for specific questions. As physicians in age management medicine, many of you recognize the importance of supplementing declining hormone levels in some baby boomers. Hormone replacement is complicated and clinically challenging. The legal aspects of hormone replacement can be similarly complicated and challenging. Understanding the laws governing hormone prescribing will help avoid legal tangles that can ruin your practice and devastate your career. HRT for Women Few areas of medicine have received more extensive study, yet yielded so much conflicting data as HRT for women. 1 Aside from the question of whether to prescribe estrogens alone or in combination with progesterone, physicians are faced with a choice of whether to prescribe brandname, commercially available hormones or bioidentical hormone replacement therapy (BHRT). Partially in response to a petition by Wyeth Pharmaceuticals, 2 the FDA warned several pharmacies that they violated federal law by compounding BHRT. Among other reasons, the FDA claimed it was unlawful to use estriol in BHRT because estriol is not an approved FDA 1 U.S. Department of Health and Human Services, National Institutes of Health National Heart, Lung, and Blood Institute, Menopausal Hormone Therapy, available at 2 On October 6, 2005 Wyeth filed a citizen s petition with the FDA, asking the agency to take action against pharmacies Wyeth believed were compounding BHRT in violation of federal law. 1

2 product. 3 The FDA also published an article on its Consumer Health Information page, titled Bio-Identicals: Sorting Myths from Facts. 4 The claim about estriol is controversial and disconcerting for physicians because the FDA s position could effectively shut down the supply of a drug many providers consider effective. The FDA s position also seems counter to the Food and Drug Administration Modernization Act (FDAMA). This law specifically governs compounding of drugs for physicians specific orders. Contrary to the FDA s position, FDAMA allows the use of drug substances that comply with the standards of the U.S. Pharmacopoeia (USP) or National Formulary (NF). 5 Estriol is listed in the USP and NF. If FDAMA still applies, a pharmacy may use estriol that meets USP or NF standards for strength and purity. The question of whether FDAMA is still governing law is the subject of continuing litigation and is summarized in the online references for this article. 6 Well-respected organizations, such as the American Pharmaceutical Association, have stated that the FDA s position is contrary to FDAMA. 7 Because physicians continue to prescribe bioidentical hormones to meet their 3 The other reasons the FDA issued warning letters included allegations the pharmacies Internet advertisements made unproven therapeutic claims and superiority claims about BHRT and the use of the term bioidentical was misleading because it was an implied claim that BHRTs are exactly the same as hormones in the body. The FDA warning letters, article, and response to the Wyeth petition can all be accessed by links on the Food and Drug Administration Website available at and at 4 Available at 5 See Food Drug and Cosmetic Act at 21 U.S.C. 353a (b)(1)(a). 6 The question as to whether FDAMA governs pharmacy compounding is complicated and continues to be the subject of litigation. FDAMA originally prohibited pharmacies from advertising compounded products. In Western States Medical Center v. Shalala, 238 F.3d 1090 (9 th Cir. 2001), the Ninth Circuit Court of Appeals struck down that prohibition as an unconstitutional restriction of speech. The Ninth Circuit also held that the advertising prohibition was not severable from the rest of the law and struck down the entire compounding section. In Thompson v. Western States Medical Center, 535 U.S. 357 (2002), the United States Supreme Court agreed with the Ninth Circuit that FDAMA violated the First Amendment, but expressly declined to rule on whether the advertising prohibition was severable. In light of the apparent absence of a law governing compounded drugs, the FDA issued the Compliance Policy Guide (CPG) section Pharmacy Compounding on May 29, 2002 (available at FDAMA permits pharmacies to use products that meet criteria in the United States Pharmacopeia even if the ingredients are not FDA approved as drugs. In contrast, the FDA narrowed the permissible components in compounded medications by saying the use of bulk active ingredients that are not components of FDA-approved drugs could be grounds for FDA sanctions. In 2006, the legal landscape changed again. A federal district judge in Texas ruled the unconstitutional section of FDAMA was severable and concluded the compounding provisions of FDAMA are still in force and effect. Medical Center Pharmacy v. Gonzales, 451 F.Supp. 2d 854 (W.D. Tex. 2006). The FDA has appealed that decision. 7 Statement From The American Pharmacists Association Regarding FDA's Action Against Compounded Menopause Hormone Therapy Drugs, January 15, 2008, available at The APhA explained: 2

3 patients medical needs, pharmacies are continuing to compound BHRT in reliance on FDAMA s language. What are the legal risks? Can the FDA sanction a physician for prescribing compounded BHRT? In its press conference, FDA officials responded to a question about whether physicians can prescribe bioidentical hormones if it s in the best interest of patients. Unfortunately, the officials gave a Kafkaesque response. On one hand, when a physician decides a patient has a specific medical need that can t be met by an FDA approved drug, the physician can prescribe compounded drugs as necessary. 8 Yet, FDA officials also said pharmacists cannot include estriol in any compounded product because it isn t an FDA approved drug. 9 Taken at face value, this means physicians can prescribe BHRT containing estriol, but pharmacies cannot compound the products. In light of the FDA s actions, what should physicians do? If you only use commercially available brands containing animal-derived conjugated estrogens, 10 there s no need to change The 1997 Food and Drug Administration Modernization Act (FDAMA) provided a number of regulations on food, drugs, devices and biological products. FDAMA listed three sources of bulk drug ingredients that could be used in compounding: drug substances that are components of FDA-approved drugs, drug substances that comply with the standards of an applicable U.S. Pharmacopoeia or National Formulary monograph, and/or drug substances that appear on a list developed by the FDA. However, in a set of guidelines that the FDA released five years later, the Agency asserted that compounded drugs should only use active ingredients that are components of FDA-approved drugs, essentially reducing the number of potential sources for bulk drug products from three to one. The Agency is using this interpretation to oppose the use of estriol in BHRT, stating it is not an FDA-approved drug. APhA does not agree with limiting pharmacy compounding to only FDA-approved drug components. The Agency guidelines fail to address the use of drugs that have been on the market since before the development of the FDA process in While not technically considered FDA-approved, acetaminophen, aspirin, phenobarbital and chloral hydrate are commonly compounded for specific patient needs based upon a physician order. 8 Transcript of FDA Press Conference on FDA Actions on Bio-Identical Hormones, January 9, 2008, at p , available at 9 Id. at pp Premarin is derived from the urine of pregnant mares and contains several different estrogens. According to the FDA, in FDA Backgrounder on Conjugated Estrogens (July 7, 2005), [p]recisely how these various estrogens contribute to the drug effectiveness has not been definitively determined. FDA Backgrounder on conjugated Estrogens Available at Pharmacies that compound BHRT, must keep fastidious records of each active ingredient and how formulations are made. In contrast, in that same paper, the FDA explained it would not approve a generic version of Premarin because the FDA does not know enough about the ingredients in Premarin: Compositional analysis of Premarin using modern analytical techniques demonstrates that it consists of a mixture of a substantial number of compounds with potential pharmacologic activity. In fact, the steroidal content of Premarin has not been completely defined. Undoubtedly, many of the compounds present in Premarin do not provide a clinically meaningful contribution to the 3

4 anything. If a patient requests BHRT or if you believe BHRT is in your patient s best medical interest, take the following steps to minimize legal risks: Work with a single pharmacy or small group of pharmacies that will dispense BHRT. Communicate with the compounding pharmacy to understand all ingredients being used and the source of the ingredients. It may be appropriate to ask for documents describing the source of the ingredients and certification that the products meet USP standards. Know whether the pharmacy complies with applicable USP standards (e.g., USP 795 for nonsterile products and USP 797 for sterile products). Ask the pharmacy about any adverse effects to its BHRT products, and document the inquiry and answer. Communicate with patients about the nature of BHRT and the differences between commercially available conjugated estrogens and BHRT. True two-way communication with patients is good medicine and good legal prophylaxis. Inform patients about the FDA s BioIdenticals: Sorting Myths from Facts. 11 Document this fact. Providing a copy is even better. If you disagree with portions of this document, discuss it with your patient. This step will help undercut patients claims that they suffered some harm by using BHRT and that their doctor never told them about the risks. 12 Human Growth Hormone (hgh) Recent criminal actions involving human growth hormone have increased awareness of the legal risks associated with this drug. Last year, after an undercover FDA agent posed as a patient seeking hgh for anti-aging effects, federal prosecutors filed criminal charges against a Reno, Nev., physician for prescribing and dispensing hgh to patients. 13 A federal jury acquitted the therapeutic effects of the drug and are best thought of as impurities. However, the clinical tests, on which the findings of the safety and efficacy of Premarin were based, were performed on the entire mixture, not on individual components. A basic understanding of Premarin's chemical composition must be achieved as a first step in adequately characterizing the product, unless a complete understanding of which components provide a clinically meaningful contribution to the therapeutic effects of the product is achieved by clinical trials alone. 11 at 12 A jury awarded three women $134 million for their claim that conjugated estrogen products (Pempro and Premarin) caused their breast cancers. The judge reduced the awards to about $58 million -- $23 million in compensatory and $35 million in punitive damage. Wall Street Journal February 20, 2008;page D7. 13 United States v. James W. Forsythe, Indictment for Violations of Title 21 United States Code, Sections 331(d),, 355(a) Causing Introduction into Interstate Commerce Unapproved New Drugs; Title 21 U.S.C. 333(e) 4

5 physician, but juries are fickle and the next physician may face a different fate. In 2004, the Kansas Board of Healing Arts revoked a physician s license, in part, for inappropriately prescribing hgh. 14 The reason for the legal problems is hgh s unique status among prescription drugs. First, hgh is not a controlled substance, but Congress has given the Drug Enforcement Agency (DEA) jurisdiction over hgh, making hgh the only noncontrolled substance the DEA investigates. The status of hgh may change. There is now a bill in Congress to make hgh a controlled substance. Second, the Food Drug and Cosmetic Act states that a person who knowingly distributes hgh for any use other than the treatment of a disease or condition approved by the FDA and pursuant to the order of a physician, is guilty of a felony punishable by up to five years in prison plus fines. The statute defines hgh to be somatrem, somatropin, or an analogue of either of them. 15 Normally, physicians can prescribe drugs for medical purposes that aren t specified in a drug s package insert. Some estimate that 40 percent to 60 percent of all prescriptions are used for offlabel purposes. 16 Despite the absence of any reference to prescribing in the law, the FDA has issued statements that hgh can only be legally prescribed for uses approved by the FDA in the drug approval process. 17 The indicated uses vary somewhat from one hgh product to another, Distribution of Human Growth Hormone; Title 18, United States Code, Section 2-Aiding and Abetting, U. Case No. 03:06:CR-147 BES-VPC, filed September 27, In the Matter of Jackie Springer, M.D. v. Kansas Board of Healing Arts, Docket No. 04HA44, Nov. 3, 2004, available at 15 The Food Drug and Cosmetic Act specifically states: [W]hoever knowingly distributes, or possesses with intent to distribute, human growth hormone for any use in humans other than the treatment of a disease or other recognized medical condition, where such use has been authorized by the Secretary of Health and Human Services under section 505 and pursuant to the order of a physician, is guilty of an offense punishable by not more than 5 years in prison, such fines as are authorized by Title 18 [federal criminal code] or both. 21 U.S.C. 333(e) 16 Ward, S. WLF and the Two-Click Rule: The First Amendment Inequity of the Food And Drug Administration's Regulation of Off-Label Drug Use Information on The Internet. Food and Drug Law Journal (1): FDA Import Alert #66-71: Detention Without Physical Examination Of Human Growth Hormone (HGH), also Known as Somatropin. Jan 23, 2007 at see also Letter from Mark Askine, Regulatory Operations Officer Division of New Drugs and Labeling Compliance Office of Compliance Center for Drug Evaluation and Research, to California Pharmacists Ass n, August 11, 2005 ( [I]t should be emphasized that NO HGH products are approved for any purpose related to reversing the effects of aging, healing athletic injuries, or enhancing sports performance. FDA is particularly concerned about these off-label uses of HGH. Knowingly distributing HGH for these purposes violates the law and, under certain circumstances, even prescribing HGH for these uses may be illegal ) (emphasis in original). Whether the FDA s position about off-label prescribing is correct is questionable and subject to dispute. This article takes the most conservative approach by 5

6 and physicians must review each product s labeling to know the FDA approved uses. In adults and children, hgh is approved to treat growth hormone deficiency (GHD). Prescribers who treat adults with GHD must carefully confirm the diagnosis with a thorough history and physical and laboratory tests. The FDA has approved specific hgh products. These products are listed in the FDA s Approved Drug Products with Therapeutic Equivalence Evaluations (aka the Orange Book). 18 Because hgh is so expensive, unscrupulous individuals may be motivated to dilute or counterfeit the drug. The FDA and Customs officials regularly seize counterfeit, contaminated or unapproved hgh. 19 Moreover, hgh cannot be compounded by pharmacies unless there s a documented good clinical reason a patient cannot use commercially available products. Federal prosecutors have indicted people for obtaining unapproved hgh for compounding. 20 What are the red flags that will increase the likelihood of an investigation? FDA investigators are most likely to focus on physicians engaging in the following activities: The physician sells hgh. Most patients who ask for hgh obtain a prescription or the drug directly. There is little, if any, documentation of exams, labs and other medical records. explaining the FDA s stated position and provides advice that would minimize legal risks is light of the FDA s position. 18 Available at 19 See e.g., FDA Press Release (P04-31)March 17, 2004, FDA and the U.S. Attorney for the Western District of Texas Announce Guilty Plea in Drug Counterfeiting Case, available at Refusal Actions by FDA as Recorded in OASIS for China (documenting several hgh products being held because they were unapproved); Combating Counterfeit Drugs: A Report of the Food and Drug Administration Annual Update, May 18, 2005 (describing an indictment issued on June 16, 2004 that charged an individual with conspiring to unlawfully distribute human growth hormone (Serostim )and trafficking in counterfeit goods. 20 Press Release, United States Attorney s Office, District of Colorado, August 29, 2007, available at (describing the indictment in U.S. v. Thomas Bader, Kevin Henry, Bradley Blum, and College Pharmacy, Inc.): According to the indictment, the defendants allegedly bought, received and distributed Chinese manufactured human growth hormone (hgh), which had not been approved by the FDA. Once the growth hormone was received in the United States, the defendants allegedly repackaged the product and sold it to physicians and their patients throughout the country. The indictment also alleges that the defendants were aware that the Chinese manufactured hgh was misbranded and unapproved for distribution and use in the United States.... [t]he FDA has never approved the distribution or use of any hgh manufactured in or imported from China.... According to the indictment, among the drugs distributed... through College Pharmacy was hgh. The indictment alleges that both defendants knowingly bought the hgh from companies that manufacture genetically derived hgh in China, including GeneScience. 6

7 hgh is sold without a prescription. Clear wrongdoing that makes it easier to obtain a conviction from a jury (e.g., profiteering, disregard of patients best interests, obtaining drugs from illegitimate sources). In addition to the federal law, some states have passed additional restrictions. Some have classified hgh as a controlled substance. 21 Therefore, check applicable state laws and regulations. Because criminal charges, not to mention conviction, can be devastating, doctors should take a conservative approach toward prescribing hgh and seek legal advice about their specific circumstances. The following guidelines may help prevent legal problems: Do not prescribe hgh for anti-aging or for any other off-label use. 22 Do not sell hgh. Let patients buy hgh from a licensed pharmacy. Conduct a thorough history and physical examination and order appropriate lab tests. Document all signs, symptoms and test results that form the clinical basis for the diagnosis of GHD. Conduct thorough follow-ups. Do not prescribe hgh to athletes. Do not let pharmacists substitute generic products or compounded hgh. Prescribe only FDA-approved forms of hgh and write dispense as written on prescriptions. Make sure the products patients receive are FDA-approved and listed in the Orange Book. Anabolic Steroids The Anabolic Steroid Control Act (ASCA), enacted in placed anabolic steroids in Schedule III of the Controlled Substance Act. 24 Schedule III drugs typically include those that 21 A few examples include: Colorado Rev. Stat , (2007) (in an odd pharmacological twist, listing human growth hormone as an anabolic steroid); Rhode Island Gen. Laws (2007) (listing human growth hormone under Schedule III); Oregon Revised Statutes (5)(j). 22 Although the FDCA only prohibits distributing hgh off-label and without a valid prescription (though not expressly prescribing off-label), it is safest to use a clinically conservative approach in prescribing hgh. Even if one wins a case after being I indicted, the fiscal, emotional, and professional costs will render the outcome a Pyrrhic victory at best. 23 Prior to enactment of the 1990 Act, anabolic steroids were approved by the Food and Drug Administration ( FDA ) for both disease and non-disease conditions. Jeffery A. Black, The Anabolic Steroids Act of 1990: A Need for Change, 97 DICK. L. REV. 131, 134 (1992). 24 For an informative explanation of the federal laws governing anabolic steroids, one should read The 2006 Steroid Report, prepared by the Steroids Working Group at the United States Sentencing Commission in March The 7

8 may lead to moderate or low physical dependence or high psychological dependence. The ASCA criminalizes the distribution of anabolic steroids for use in humans other than the treatment of a disease or other recognized medical condition. The law defines anabolic steroid broadly to mean any drug or hormonal substance, chemically and pharmacologically related to testosterone (other than estrogens, progestins, corticosteroids and dehydroepiandrosterone) 25 The definition lists more than 50 specific compounds. Of course, anyone who prescribes an anabolic steroid must have a DEA registration number and a state license to prescribe. Some states also require a separate controlled substances license. Federal regulations require that a prescription for a controlled substance must be issued for a legitimate medical purpose by an individual practitioner acting in the usual course of his professional practice. 26 The question of what constitutes a legitimate medical purpose has been the subject of several court decisions. Some courts have held that a national standard governs the meaning of legitimate medical practice. 27 Recently though, the United States Supreme Court reasoned that Congress did not intend to impose a national standard for what constitutes legitimate medical use of a controlled substance. 28 Whether a state or federal standard applies, physicians must look at their state laws to govern their prescribing. States have generally passed stricter laws for regulating anabolic steroids and often specifically exclude certain uses from legitimate medical purposes. For example, Oklahoma law states: A valid medical purpose for the use of anabolic steroids or human growth hormones shall not include bodybuilding, muscle enhancement or increasing muscle bulk or strength of a person who is in good health. 29 To minimize legal risks, heed the following: report was issued in response to Congress s directive to review and adjust federal sentencing guidelines for crimes related to anabolic steroids U.S.C. 802(41)(A) C.F.R See United States v. Vamos, 797 F.2d 1146, 1151, 1153 (2d Cir. 1986) (Controlled Substances Act incorporates the standard of professional practice generally recognized and accepted in the United States ), cert. denied, 479 U.S (1987); United States v. Hayes, 794 F.2d 1348, (9th Cir. 1986) ( the standard of medical practice generally recognized in the country ), cert. denied, 479 U.S (1987); United States v. Norris, 780 F.2d 1207, 1209 & n.2 (5th Cir. 1986) (same as Vamos); United States v. Daniel, 3 F.3d 775, 778 (4th Cir. 1993) (same), cert. denied, 510 U.S (1994); Kevin F. O Malley et al., Federal Jury Practice and Instructions (Criminal) 64.16, at 428 (5th ed. 2000) (same). 28 Gonzales v. Raich, 126 S.Ct. 904 (2005) (upholding the use of controlled substances to assist suicide under the Oregon Death with Dignity Act based on interplay between scope of federal Controlled Substances Act and state law) Okl. St

9 Do not prescribe anabolic steroids to enhance athletic performance or to build muscle, except for a condition in which building muscle is important to health, such as cancer or AIDS. Do not sell anabolic steroids. Let patients buy them from a licensed pharmacy. 30 Conduct a thorough history and physical examination, and order appropriate lab tests. Document all signs, symptoms and test results that form the clinical basis for the diagnosis of a disease or other medical condition for which anabolic steroids are medically indicated. Conduct thorough follow-ups. Do not prescribe hgh to athletes. Read, understand and follow state laws and regulations. Although federal and state laws may not all be models of clarity, physicians who prescribe hormones must understand those laws and use common-sense procedures to comply with them. Most of the suggestions in this article boil down to keeping focused on providing the best medical care for patients and ensuring the products dispensed to patients comply with applicable laws. Finally, stay informed about state and federal laws in this area. Like the state of medical science, laws continually change. (Bill: need a bio about you) Here is the firm s bio for me and a short version below. Bill Stilling is a shareholder at the law firm Parsons Behle and Latimer where he chairs the firm's Health and Life Sciences Practice Group and is a member of the Litigation Department. His practice emphasizes drug and medical device law, dietary supplements and nutraceuticals, health care and life science regulatory issues, intellectual property, professional licensing, privacy law, health care fraud and abuse, and complex commercial litigation. Bill is based in Salt Lake City, but spends part of his time in the firm s Las Vegas and Reno, Nevada offices. In addition to his law practice, Bill is an associate professor (clinical) in the Department of Pharmacotherapy at the University of Utah College of Pharmacy where he teaches courses in drug law and health care ethics. 30 Cf. American Medical Association Code of Medical Ethics E-8.06 Prescribing and Dispensing Drugs and Devices, available at 9

10 Mr. Stilling graduated from the University of Utah, College of Pharmacy in 1983, received a master's degree in Pharmacy Administration in 1989, and graduated from the University of Utah College of Law in