References for Legal Prophylaxis

References for Legal Prophylaxis
By William J. Stilling, RPh, MS, JD
Vol. 3, Issue 6
Pp. 59-62

1. U.S. Department of Health and Human Services, National Institutes of Health National Heart, Lung, and Blood Institute, Menopausal Hormone Therapy, available at http://www.nhlbi.nih.gov/health/women/pht_facts.pdf.

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.

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 http://www.fda.gov/bbs/topics/NEWS/2008/NEW01772.html and at http://www.fda.gov/cder/pharmcomp/default.htm.

4. See Food Drug and Cosmetic Act at 21 U.S.C. §353a (b)(1)(A).

5. 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 460.200 Pharmacy Compounding on May 29, 2002 (available at http://www.fda.gov/OHRMS/DOCKETS/98fr/02D-0242_gdl0001.pdf).  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.

6. Statement From The American Pharmacists Association Regarding FDA's Action Against Compounded Menopause Hormone Therapy Drugs, January 15, 2008, available at http://www.pharmacist.com/AM/Template.cfm?Template=/CM/ContentDisplay.cfm&ContentID=14951.  The APhA explained:

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 1938.  While not technically considered FDA-approved, acetaminophen, aspirin, phenobarbital and chloral hydrate are commonly compounded for specific patient needs based upon a physician order.

7. Transcript of FDA Press Conference on FDA Actions on Bio-Identical Hormones, January 9, 2008, at p.  37-38, available at  http://www.fda.gov/bbs/transcripts/transcript010908.pdf.

8. Id.  at pp.  6-7.

9. 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 http://www.fda.gov/CDER/news/cebackground.htm.  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 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.

10. at http://www.fda.gov/consumer/updates/bioidenticals010908.html.

11.   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.

12. 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) 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, 2006.

13. In the Matter of Jackie Springer, M.D.  v.  Kansas Board of Healing Arts, Docket No.  04HA44, Nov.  3, 2004, available at http://www.ksbha.org/boardactions/Documents/springerinitialorder.pdf.

14.  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)

15. 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.  2001 56(1): 41-56.

16. FDA Import Alert #66-71: Detention Without Physical Examination Of Human Growth Hormone (HGH), also Known as Somatropin.  Jan 23, 2007 at http://www.fda.gov/ora/fiars/ora_import_ia6671.html; 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 explaining the FDA's stated position and provides advice that would minimize legal risks is light of the FDA's position.

17. Available at http://www.fda.gov/cder/ob/.

18. 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 http://www.fda.gov/bbs/topics/news/2004/NEW01036.html; 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.

19. Press Release, United States Attorney's Office, District of Colorado, August 29, 2007, available at http://denver.fbi.gov/dojpressrel/2007/hormoneimportations082907.htm (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.

20. A few examples include: Colorado Rev.  Stat.  §§ 18-18-102, 18-18-205 (2007) (in an odd pharmacological twist, listing human growth hormone as an anabolic steroid); Rhode Island Gen.  Laws § 21-28-2.08 (2007) (listing human growth hormone under Schedule III); Oregon Revised Statutes 855-080-0023(5)(j).

21. 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.

22. 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).

23. 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 2006.  The report was issued in response to Congress's directive to review and adjust federal sentencing guidelines for crimes related to anabolic steroids.

24. 21 U.S.C.  §802(41)(A).

25. 21 C.F.R. § 1306.04.

26. 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. 1036 (1987); United States v. Hayes, 794 F.2d 1348, 1351-1352 (9th Cir. 1986) ("the standard of medical practice generally recognized in the country"), cert. denied, 479 U.S. 1086 (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. 1130 (1994); Kevin F. O'Malley et al., Federal Jury Practice and Instructions (Criminal) § 64.16, at 428 (5th ed. 2000) (same).

27. 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).

29. Cf. American Medical Association Code of Medical Ethics E-8.06 Prescribing and Dispensing Drugs and Devices, available at www.ama-assn.org/apps/pf_new/pf_online?category=CEJA&assn=AMA&f_n=mSearch&s_t=&st_p=&nth=1&