1. Bio-identical Hormone Therapy: What’s the Harm? Bruce Patsner, M.D., J.D. Professor, Health Law & Policy Institute, University of Houston Law Center NAMS Annual Meeting September 26, 2008

2. Disclaimer The views expressed in this presentation are those of the author only. All information is in the public domain. My views do not represent those of the University of Houston Law Center, The United States Food and Drug Administration, or any other government employee

3. Putting Bio-identical Hormone Therapy (BHT) in Perspective BHT is a major issue at NAMS and every ACOG meeting every year There is NO WAY to talk about this subject without talking about the medical profession itself Are there “problems” with BHT? If so, what are the solutions?

4. Some Basic Definitions Bio-identical – no set definition Natural – neither artificial nor pathologic Pharmacy compounding – defined by both FDA and Pharmacy industry; at core is the “triad” relationship New drug – defined by 1938 FDCA

5. What Are Bio-identicals? Not a scientific term, and no uniform definition in any medical dictionary Molecularly very similar or identical to endogenous hormones; plant-derived from soybean or yam “Individualized exact doses” to replicate homeostatic hormone levels of Estrogen, Progesterone, Testosterone Dosage is adjusted according to salivary or blood hormone levels, unlike commercial HR which is adjusted based on symptom relief Purported anti-aging, sexual vibrancy and energizing effects are similar to structure/function claims made for dietary supplements rather than disease treatment/prevention claims made for drugs

6. Some Basic Facts First Pharmacy compounding of BHT is now a multi-billion dollar a year industry Bio-identical HR drugs are prescription drugs, not over-the-counter. Physicians are (or should be) always part of triad. Absent active participation by the medical profession, this industry could not prosper or function the way it has FDA has been fighting for decades over whether it has jurisdiction over pharmacy compounding at all, and to what degree

7. Why the Surge in Prescriptions for Bio-identicals from Patient POV? Response to widely publicized results from 2002 WHI Suspicion of traditional medicine Dislike of big Pharmaceutical companies Perception it’s a safer alternative Natural is equated with safer Wider and more aggressive advertising, via internet and other media Patient preference for alternative medicine. Begs question of just how “alternative” it is Least likely reason – patients still symptomatic on properly prescribed commercial HR products

8. Facts to Frame the Harm Q… Little or no substantive data comparing BHT with commercial HT. The studies all have deficiencies Given uncertainty over whether FDA really can regulate, no real incentive on the supply side for anyone to do randomized, controlled or comparative studies it would be great if someone did Almost all potential patients could obtain adequate medical therapy/symptom relief with commercial HR were they prescribed properly and patients so inclined to take them

9. The Problems with BHT No tested in good clinical trials, and no endometrial safety data “Natural” does not really equal “safer” No clinician or patient package inserts documenting safety/efficacy, and no black box warnings No uniform manufacturing standards. In one study 25% of compounded products tested failed quality control testing vs. 2% of commercially manufactured drug products No formal review of accuracy of advertised claims This is A LOT of “Nots”. Will it even matter to those determined to take these products?

10. There Would Be No Harm If the Following Were All True Patients fully informed of true risks/safety Physicians fully aware of limitations on safety/efficacy data All advertising of risks/benefits is completely truthful The pharmacies all product a consistent, excellent product and did not attempt to practice medicine All prescriptions were completely legitimate Salivary hormones levels actually meant something and were inexpensive to boot BHT were proven as safe and effective as other HR FDA found more important things to regulate

11. What Harm/Potential Harms, and Harm to Whom? To patients? To prescribing physicians? To medical societies? To the medical profession? To commercial drug manufacturers? To compounding pharmacies and their industry? To regulatory agencies such as FDA and state pharmacy/medical boards? To the reputation of our federal courts?

12. Discuss Data Before Harms: Likely Bottom Lines BHT may be just as effective as commercial HR, and likely is so though never proven to be BHT never been shown to be safer or more effective BHT should be just as safe as commercial HR, but there’s no reason for it to be any safer than any other HR If all this is true, why are physicians writing so many prescriptions? Because medicine is more than an art, it’s also a trade/business

13. Summary of Recent Literature Cirigliano M. Bioidentical Hormone Therapy: A Review of the Evidence. J. Women’s Health 16: 2007 Moskowitz D. A Comprehensive Review of the Safety and Efficacy of Bioidentical Hormones for the Management of Menopause and Related Health Risks. Alternative Medicine Review 2006 Fugh-Berman A et al. Bioidentical Hormones for Menopausal Hormone Therapy: Variation on a Theme. J. Gen. Internal Med. 22: 2007. This one points out that use of salivary hormone levels may result in use of doses that are higher than the least effective dose (LED), an approach favored by both medical societies and FDA Guidance Documents.

14. Practices Which Don’t Measure Up The salivary hormone level thing. Let’s call it friendo – this is junk medicine Promoting BHT as safer, more effective, or cancer-preventive Promoting BHT as a wholesale replacement for commercial HR products. This is not compounding. Not taking enforcement actions against those pharmacies which are the biggest offenders State boards not pursuing fraudulent activity

15. How Do Some Compounding Pharmacies Hurt Patients? “practice medicine” by adjusting doses of BHT independent of physicians. Note: something is needed to adjust doses in order to claim that the therapy is individualized Promote these products globally to any patient as a replacement for commercial HR products which are safe and effective for most patients Make false claims regarding safety/efficacy Overcharge for these meds? Largest compounding pharmacies just drug manufacturers in disguise Continued litigation by some pharmacies over 1 st amendment issues now runs risk of eliminating availability of compounded drugs for many patients

16. How Do Physicians Hurt Patients? By taking patients off meds with known safety and efficacy profiles to place them on BHT where these are unknown Waste scarce patient financial resources on meaningless hormone level testing and more expensive BHT that offers no therapeutic advantage. Just because patients want it and are willing to pay for it does not mean you have to go along with it. How about medical decision making – prescribe only when it’s indicated

17. How Can Federal Courts Hurt Patients? By holding that all compounded prescription drugs are new drugs, as defined by the 1938 FDCA In the long run this could restrict availability of many kinds of compounded prescription drug products Could theoretically require pharmacies to do clinical trial to support an NDA to meet new drug approval requirements Could force pharmacies into doing IND applications in order to demonstrate that they are planning on submitting an NDA. No pharmacy can really afford to do either of these

18. Update on Federal Litigation Over Pharmacy Compounding Historically most drugs were compounded drugs; now only 8% FDA originally considered all compounded drugs to be new drugs, but left much of this practice alone and intent only to intervene when pharmacies were manufacturing, not compounding 1997: FDAMA abandons FDA’s long-standing position on compounding but creates bigger problems with FDA’s attempt to restrict promotion of specific compounded products, as opposed to pharmacies just advertising that they compound Results in Western States litigation which FDA loses FDA then back to “enforcement discretion” approach to selectively intervene; pharmacy industry still takes position compounding is integral part of normal practice of pharmacy and none of FDA’s business The problem is the litigation doesn’t stop

19. Most Recent Federal Court Decision Continues to Create Problems Med Ctr Pharm v. Gonzales (W.D. Tex 2006) – holds compounded drugs are not “new drugs” in a bench trial. FDA loses, but appeals Med Ctr Pharm v. Mukasey (5 th Circuit 2008) reverses but muddies the waters 1. Compounded drugs ARE new drugs and FDA can regulate, BUT 2. Congress did not intend to deem all compounded drugs new drugs, and 3. Disagrees with 9 th Circuit and holds that §503A of FDAMA does remain in effect (even FDA had agreed it was no longer in effect) and that the advertising restriction sub-section could be split off from the rest of the section (something the 9 th Circuit said could not be done) and that alone was invalid All of this leaves us where, exactly? Confused yet? They are…

20. Medical Center Pharmacy v. Mukasey (5 th Circuit 2008) Importance relates to Section 503A of FDCA In the 9 th Circuit territory (California, Nevada, Arizona, Oregon, Washington) pharmacists cannot claim protection of this section (under FDAMA FDA ceded jurisdiction over compounding to the states), whereas they can in 5 th Circuit Status of all of this in the rest of the U.S. now uncertain because of split in Appellate Courts These cases not originally driven by FDA but rather by compounding pharmacies who claimed FDA attempts to restrict their advertising of specific compounded drug products violated their commercial speech rights under the 1 st amendment The problem is that they have now jeopardized all of pharmacy compounding because this will likely go up to the Supreme Court and how they will decide is not known. This was not the case when I talked at NAMS on this in 2006

21. Implications: if compounded drugs are “new drugs” by ruling FDA has real jurisdiction over all of it If sold compounded drug not supported by an approved NDA can either be seized or pharmacy enjoined from making and selling. End result: some patients won’t get these meds No pharmacy has $800K lying around to invest in an NDA application or the millions it will take to do clinical trials to prove they are safe and effective Pharmacy compounding could cease to exist FDA will likely “selectively enforce” to prevent this, and the whole litigation cycle will start all over again since enforcement criteria will be somewhat arbitrary (i.e. if you’re making too much then you are a manufacturer, not a traditional compounding pharmacy)

22. Enough about Judicial Harm. Can Patients Hurt Themselves? Patients have this right. Physicians do not. Patients can, and do, ask for medications and procedures that are either worthless, harmful, or frivolous. Look at dietary supplements, plastic surgery, and C-Section on demand. It is the medical profession’s job to place real limits on this. It is our fiduciary duty to do so. Also, it’s bad enough when patient’s waste their own money. Indirectly, they are wasting others’ as well The tradeoff: patient autonomy vs. evidence based medicine. What do we stand for as a profession, really?

23. A final harm: Medical Information via the Internet It’s totally unregulated FDA has not even begun to really engage this issue, nor has the medical profession (or anyone else) really Supreme Court takes the position that information is better than restriction of information Lots of horribly false or misleading info out there; the latter is ok according to courts if there is a disclaimer even though evidence strongly suggests these are worthless BUT, this is also an opportunity for medicine – medical societies, our profession – to seize the initiative and assert some good information control.

24. What Must the Pharmacy Profession Do to Help Itself? Better self-regulation so the feds and state boards don’t step in Get rid of false and misleading advertising Reign in the worst offenders; they are ruining it for everyone else. It’s no different than the Ephedra/dietary supplement debacle

25. What Must Medicine Do, or Try to Do, To Correct Itself? Real effort at self-regulation. A license to practice medicine is not a license to practice junk medicine Make a determined effort to do the comparative trials to evaluate BHT claims Medical societies should consider issuing opinions about setting limits on patient demands. We are not selling pizza. Full disclosure to patients of your financial investments in labs and pharmacies wrapped up in the BHT process As for the physicians who genuinely believe everything that’s out there about BHT as well as the pseudoscience behind salivary hormone levels, I’m not sure what we can do about this

26. What Must Federal Courts Do? Sigh… It’s always a thrill when federal courts weigh in on medical matters. Between abortion and autism, there’s no telling where things are headed (and that’s just the a’s…) It is possible the status of pharmacy compounding will now end up in front of the Supreme Court. If it does not, we’ll have different regulatory systems in different parts of the U.S.

27. What Should State Boards Do? Protect their citizens by taking enforcement actions against marginal and fraudulent medical and pharmacy practices Police fraudulent claims in ads The First Amendment offers no protection for lies

28. This is Not Just a U.S. Issue The health issues are a potential problem for all countries in North America even if the costs of compounded BHT and the manner in which the government regulates them is not. I’m open to suggestions from members of NAMS outside the U.S. on how to approach this issue

29. Summing Up the Harms Economic (for patients) Patient Safety (for patients). Need data Regulatory – for government and courts. The latter are confused, and confusing. FDA – what’s the point if you’re only going after the small fish? Reputation – for medical profession

30. Where We Are Likely Headed A U.S. Supreme Court decision to resolve the issue Compounding pharmacies will try to stay under the radar screen if they are smart, but it may be too late because of continued litigation in federal court Medical societies such as NAMS will continue to do the correct thing by continuing physician and patient education. Perhaps more of an internet presence with very attractive, and the best, websites. Medical profession self-regulating: don’t count on it, but greater effort to kill medicine with no good evidentiary basis would be a nice start

31. Thank You “Qui tacet consentire videtur”* He who is silent is taken to agree