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On September 5th, the FDA issued a proposed rule rejecting eleven substances nominated by the American Association of Naturopathic Physicians (AANP) and like-minded organizations for use in drug compounding, including curcumin and cesium chloride. Curcumin was the active ingredient in an intravenous infusion that killed the patient of a California-licensed naturopathic doctor. Cesium chloride is a dangerous and ineffective naturopathic and “integrative” cancer treatment, previously the subject of an FDA safety alert. If finalized, which seems highly likely considering the solid science behind it, the rule will prohibit the use of these and other substances in compounded drugs.

(The entire list of the AANP’s nominated substances can be found in this document, under “Tab 2a, Cesium Chloride Nominations.” Links to substance nominations, the FDA’s evaluations, and the Pharmacy Compounding Advisory Committee’s analyses and recommendations are found in the proposed rule.)

The proposed ban comes on the heels of a recent FDA rule, several years in the making, establishing criteria for determining which substances can be used in compounded drugs. Based on the new criteria, several substances, like piracetam, also nominated by the AANP, have already been banned.

Compounded drugs are an exception to the Food, Drug and Cosmetics (FD&C) Act’s requirement that prescription drugs undergo extensive safety and efficacy testing before going on the market, as well as mandated good manufacturing practices and adverse event reporting. In the particular type of compounding that is the subject of the FDA’s new criteria, sometimes called traditional compounding, pharmacies and physicians (including naturopaths where they are state-licensed to do so) can create drugs in-house as long as the drug is made for an individual patient pursuant to a prescription (including prescribing by a naturopath where, again, permitted by state law.) When used appropriately, compounding can serve a useful purpose, such as allowing a pharmacist to make a drug in liquid form for a patient who cannot swallow capsules or without substances to which a patient is allergic.

The FDA has had the authority to regulate the substances used in making compounded drugs for years but, for various reasons, it chose to leave oversight of traditional compounding mostly to the states, which regulate the practices of medicine and pharmacy, as opposed to the drugs they prescribe and sell.

This regulatory void created a business opportunity for naturopaths and like-minded fringe medical practitioners, as well as the compounding pharmacies catering to them and their dubious prescriptions. Freed from the normal safety and efficacy evidence requirements for prescription drugs, these practitioners were able to create drugs based on scanty evidence or, in some cases, crackpot “theories” of disease processes at odds with science. This transformed compounding from a useful service to what is essentially experimentation on human subjects without the safeguards of a clinical trial or scientifically meaningful results.

In 2013, the FDA finally decided to exercise its oversight authority and invited nominations of bulk drug substances for inclusion on a list the agency would promulgate specifying which substances could legally be used in compounding, called the “503A Bulks List,” after Section 503A of the FD&C Act. It would evaluate these substances with the help of an expert panel, the Pharmacy Compounding Advisory Committee (PCAC), comprised of physicians, pharmacists, and industry and consumer representatives, including those with academic appointments at medical and pharmacy schools and hospital pharmacists from Duke and St. Jude’s Children’s Hospitals. The FDA would then decide, via the cumbersome and time-consuming administrative rulemaking process, which bulk drug substances could, and could not, be used in traditional compounding.

This process resulted in the new proposed rule, which is now open for public comment. (Instructions on submission of comments are in the proposed rule.) It lists 25 substances for exclusion from, and five for addition to, the 503A Bulks List. While some on the exclusion list, such as freeze-dried aloe vera and nettle, might be used by naturopaths and “integrative” doctors in their practices, they were nominated by other organizations, such as compounding pharmacies. We’ll focus here on the substances nominated by the AANP, along with their comrades in the “integrative” medicine biz, as it gives us insight into the vast divide between what they consider appropriate therapies and the actual evidence of safety and effectiveness for those therapies. And, as noted by the FDA,

Keep in mind that the FDA’s evaluation of the nominated substances is far less rigorous and less comprehensive than the Agency’s review of drugs as part of the new drug approval process.

It is ironic that naturopaths eschew FDA-approved prescription drugs in favor of their own “natural” treatments when, in fact, those treatments can consist of prescription drugs, in compounded form, that have not, and likely cannot, met the safety and efficacy standards of the drugs they reject.

The rejects

With that, let’s look at a brief summary of the reasons the FDA rejected the AANP’s nominations. (Other organizations, like compounding pharmacies, took the lead in making some of the nominations on the AANP’s list.)

7-keto DHEA: evaluated for treatment of Raynaud’s phenomenon and weight loss (also appears to be promoted by alternative practitioners for “adrenal fatigue”, for which the FDA did not evaluate it, presumably because it is a fake disease); could not adequately assess safety; insufficient data to establish effectiveness. Pharmacy Compounding Advisory Committee recommendation: don’t include on 503A Bulks List.

Acetyl-L-carnitine: evaluated for Alzheimer’s disease, chemotherapy-induced peripheral neuropathy, and hepatic encephalopathy; may affect blood clotting and pose risk for seizures; insufficient evidence of effectiveness. PCAC: don’t include.

Alanyl-L-glutamine: evaluated for nutrition support and reducing infectious complications in critically ill and surgical patients; toxicity concerns with potential impurities such as heavy metals; limited evidence of effectiveness. PCAC: don’t include.

Artemisinin: evaluated for malaria, helminthic infections, protozoal infections, stomach ulcers and cancer; short half-life and poor oral bioavailability; significant drug-drug interactions, serious adverse events, including drug-induced hepatitis with repeat dosing; likely effective for malaria but FDA-approved drugs available for treatment (a factor the FDA considers in evaluation). PCAC: don’t include.

BWSE [nominated as Boswellia]: evaluated for rheumatoid arthritis (RA) and osteoarthritis (OA); because it is a naturally derived botanical substance, physical and chemical characteristics can vary; may induce abortion; associated with gastrointestinal adverse events; has coagulant effect; may improve OA but not effective in inhibiting RA; are numerous FDA-approved drugs for these conditions. FDA notes that Boswellia has been used “for millennia particularly in Ayurvedic and traditional Chinese medicine” (proving, once again, that “thousands of years” of use does not guarantee safety). PCAC: don’t include.

Cesium chloride: evaluated for use in cancer; significant safety concerns, including hypokalemia, seizures, QT prolongation, cardiac arrhythmias; no evidence of effectiveness in preventing or treating cancer; numerous FDA-approved drugs for cancer. PCAC: don’t include.

Chrysin: evaluated for use as an aromatase inhibitor, FDA notes it is also compounded for bodybuilding, “men’s health”, and testosterone replacement; potential for mutagenicity and neurotoxicity; poor oral bioavailability and rapid metabolism and elimination; insufficient information to evaluate safety; no clinical data that chrysin effective in cancer treatment; FDA-approved aromatase inhibitors and testosterone replacement therapies available. PCAC: don’t include.

Curcumin: evaluated for familial adenomatous polyposis, gastric metaplasia, oral leukoplakia; FDA notes use for eczema and thrombocytopenia; poor bioavailability; lack of exposure-response for safety; lack of uniformity in product; lack of well-designed chemical trials; insufficient evidence effective for proposed conditions; risk of use in lieu of, or delay of, FDA-approved treatments. PCAC: don’t include.

Germanium sesquioxide: evaluated for treatment of cancer; can include impurities with significant toxicities, specifically inorganic germanium salts; limited safety information; prolonged use associated with renal failure and death; currently a restriction on importation of all germanium compounds except for semiconductors; very little clinical data on effectiveness in treating cancer; FDA-approved treatments available. PCAC: don’t include.

Glycyrrhizin: used to refer to a variety of licorice extracts; evaluated for treatment of hepatitis C by intravenous administration; association between glycyrrhizin and serious pseudo-hyperaldosterone effects well-established; no demonstrable antiviral effect; used for curative and flavoring “for 4,000 years”. PCAC: don’t include.

Rubindium chloride: evaluated for cancer treatment; insufficient information to determine whether use would be safe or effective; numerous FDA-approved drugs for cancer. PCAC: don’t include.

Vanadyl sulfate (on Bulks List of nominated substances as vanadium): evaluated for use in treatment of diabetes, hyperlipidemia and heart disease and for cancer prevention; data suggest potential for high toxicity profile; limited human safety data; insufficient evidence for effectiveness; no clinical effectiveness data for treatment of heart disease or cancer found; FDA-approved drugs available for these conditions. PCAC: don’t include.

The AANP’s nomination of vanadyl sulfate, joined by McGuff Compounding Pharmacy Services, the Integrative Medical Consortium (discussed below), and the Alliance for Natural Health USA, a faux “grassroots” organization promoting, among other things, “vaccine choice,” is an interesting case study in just how dangerous these people can be and how lacking in evidence their therapies are, as evidenced by the PCAC’s discussion of their nomination. One can only wish that state legislators, who credulously license naturopaths and give them a broad scope of practice, would be as astute in evaluating them.

The nomination listed “slow intravenous” as the “anticipated route of administration” for vanadyl sulfate, which raised serious concerns for Robert J. Smith, M.D., Professor of Medicine and Health Services at Brown University, who said he was “very familiar” with the substance, including human studies of its use in diabetes treatment. He was “very concerned about potential toxic effects” including the fact that it might “promote cell growth and might promote malignancy”. As well,

I have difficulty understanding what the IV use would be. . . . If we’re looking at an intravenous dose, then I think we have to ask what that might mean for vascular cells or . . . for the myocardium? And we have no data.

Michael A. Carome, MD, a representative from Public Citizen, added that

As a nephrologist, the fact that it accumulates in the kidneys and causes clearly in animals nephrotoxicity . . . I share your concerns that the toxicity signal here and the safety signal here is very, very strong and very worrisome.

Another physician, Jurgen Venitz, MD, PhD, a professor from Virginia Commonwealth University’s School of Pharmacy, noted that it also accumulates in the bones and has a half-life of 10 days.

Dr. Venitz did manage to add a note of levity to the discussion. Upon Dr. Smith’s inquiry about IV use, Dr. Venitz noted that, as the nominator (the AANP et al.) was not present,

The only thing I know is what’s on the nomination document. Let me just read it. “Vanadium is used for diabetes, hyperglycemia, hyperlipidemia, heart disease, edema, improving athletic performance in weight-training, preventing malignant cell development. It is also used for treating tuberculosis, diabetes, syphilis, and a form of microcytic anemia, chlorosis. It’s also used as a source trace mineral supplementation in vanadium-deficient cases.” And you can probably can clean your house with it too.

At which point the transcript notes:

Laughter.

A group calling itself the “Integrative Medicine Consortium”, has joined with the Academy of Integrative Health and Medicine, and two compounding pharmacies, Medisca, and McGuff Compounding Pharmacy Services, in an effort to block the evidence-based consideration of its compounding favorites by the FDA because, they say, apparently without irony, that “patients’ health is being compromised”. In addition to the AANP, the Consortium includes a couple of Pseudomedical Pseudoprofessional Organizations that have appeared on SBM before: the American Academy of Environmental Medicine and the American College for the Advancement in Medicine, as well as the International College of Integrative Medicine, a group that pushes chelation therapy for supposed “heavy metal toxicity”. All of the Consortium’s members are on Quackwatch’s list of Questionable Organizations. The Academy of Integrative Health and Medicine sponsors a “fellowship” program, not ACGME accredited, that allows one to sit for the American Board of Integrative Medicine exam and become board-certified in the dubious specialty known as “integrative medicine“. All of these obviously have a considerable financial interest in the 503A Bulks List.

In addition to filing a Citizens Petition protesting the FDA’s new compounding criteria, the group is trying to raise $100,000 for their fight and enlist their “grateful patients” in their campaign, with the possibility of another $150,000 needed to file a federal lawsuit. They also want Congress to “stop FDA’s overreach”, an effort that has been at least partially successful with the filing of H.R. 1959.

While commendable, the FDA’s actions will only go so far in curbing the use of unproven and sometimes dangerous therapies by naturopaths and “integrative” physicians. As long as states allow the licensure of naturopaths and protect physicians who use CAM in their practices, and the medical profession continues to embrace “integrative medicine”, patients will pay the price.

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Posted by Jann Bellamy

Jann J. Bellamy is a Florida attorney and lives in Tallahassee. She is one of the founders and Board members of the Society for Science-Based Medicine (SfSBM) dedicated to providing accurate information about CAM and advocating for state and federal laws that incorporate a science-based standard for all health care practitioners. She tracks state and federal bills that would allow pseudoscience in health care for the SfSBM website.  Her posts are archived here.