The FDA recently issued a final rule, several years in the making, establishing criteria for determining which substances can be used in compounded drugs. Naturopaths and fringe medical practitioners have exploited decades of FDA inattention to create what is, in effect, a shadow drug manufacturing industry which operates free of the Food, Drug & Cosmetics Act’s (FD&C Act) safety and efficacy requirements for prescription drugs. Based on the new criteria, several substances previously used in compounded drugs have been banned and unfavorable evaluation of other substances by experts portends the prohibition of even more, causing the American Association of Naturopathic Physicians (AANP) and others in the CAM industry great anxiety.
Compounded drugs are an exception to the 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 rule, 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. 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.
(Note that hospital compounding and compounding in larger quantities by outsourcing facilities are the subject of different FDA requirements and not part of our discussion here.)
The FDA has had the authority to regulate the substances that could be used to make 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.
Not surprisingly, this led to some tragedies. A patient died after a naturopath injected her with compounded curcumin to remedy her eczema, one of many conditions he advertised as treatable with IV curcumin. Another patient was killed upon her 13th infusion of a compounded solution containing selenium, prescribed by her naturopathic doctor for wound healing post-cancer surgery. IV chelation therapy with compounded products, prescribed for dozens of unproven uses, has also caused fatalities. Injections of compounded cesium chloride, promoted as a quack cancer treatment by naturopaths and some “integrative” physicians, resulted in severe adverse events, including death. Of course, without adverse event reporting requirements, we cannot know the true incidence of harm.
A well-publicized 2012 outbreak of fungal meningitis traced to compounded drugs caused Congress to enact a new law governing large-scale compounding, giving the FDA increased regulatory authority. The FDA took this opportunity to take a fresh look at its authority over traditional compounding as well. In 2013, the FDA invited interested persons to nominate 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.
Based on these nominations, for which supporting evidence was required, the FDA created three categories:
- Substances nominated with sufficient evidence and under evaluation for the 503A Bulks List.
- Substances that raised significant safety concerns.
- Substances nominated without adequate supporting evidence.
Pending further review and a final ruling by the FDA, only Category 1 substances could be used in compounding without risk of regulatory action. This caused great consternation among naturopaths, who griped, among other things, that they were too busy to provide the evidence of safety and efficacy necessary to get numerous substances onto the Category 1 list. The FDA was unmoved.
In 2016, the FDA issued a proposed rule that enumerated the circumstances under which a substance could be used in compounding, prompting further griping from naturopaths. In March of this year, the FDA issued its final rule, making its criteria legally binding. Needless to say, the naturopaths, “integrative” physician groups, a few compounding pharmacies, and their sympathizers are unhappy. In fact, they appear to be in somewhat of a panic, a topic we will return to in a moment.
(Note that the new rule applies only to the 503A Bulks List. Substances that comply with a USP or NF monograph and substances that are components of FDA-approved drugs can also legally be used in compounding.)
The FDA’s new criteria are:
- the physical and chemical characterization of the substance;
- any safety issues raised by the use of the substance in compounded drug products;
- the available evidence of effectiveness or lack of effectiveness of a drug product compounded with the substances, if any such evidence exists;
- historical use of the substance in compounded drug products including information about the medical condition(s) the substances has been used to treat and any references in peer-reviewed medical literature.
To any reasonable person, these would seem to be perfectly sound criteria. However, among other objections, the CAM crowd wanted the FDA to consider historical use dispositive in some cases, to include substances that are generally recognized as safe for use in food, didn’t want the FDA to consider the seriousness of the condition the compounded product is proposed to treat or the fact that an FDA-approved drug was available to treat a condition, the “unreasonable” high standards for evidence set by the FDA, and the FDA’s refusal to automatically include substances that are dietary supplements and homeopathic remedies. The FDA was also accused of “unfairly screen[ing]” and cherry-picking the evidence, misrepresentation, and manipulation.
The dissenters also objected that no naturopaths were included on the Pharmacy Compounding Advisory Committee (PCAC), the group of experts established to advise the FDA on the 503A Bulks List, and that “neither the FDA nor the PCAC has the necessary expertise to make judgments on the nominated bulk drug substances.” Actually, the PCAC has expertise in spades. It is comprised of physicians, pharmacists and a veterinarian with academic appointments at medical, pharmacy, and veterinary medicine schools, hospital pharmacists from Duke and St. Jude’s Children’s Hospitals, representatives from the compounding industry and the FDA, and consumer representatives.
Fortunately, the FDA rejected each of these objections.
The FDA, after consideration of the evidence, also promulgated a rule placing six substances on the 503A Bulks List and rejecting four others. (For you chemistry and pharmacy fans out there, included were Brilliant Blue G, and, for topical use only, cantharidin, diphenylcyclopropenone (DCPC), acetyl-D-glucosamine, Squaric acid dibutyl ester, and thymol iodide. Excluded were oxitriptan, piracetam, silver protein mild, and tranilast.) Notably, the FDA will include and exclude substances from the list via rulemaking, meaning the agency will have to publish a proposed rule and accept public comment on each substance included or excluded.
While only ten substances have made it through the entire FDA approval process, a number of substances nominated by the AANP or otherwise supported by the naturopathic community have been voted down by the PCAC, some with unanimous “no” votes.
- Quercetin dihydrate
- Cesium chloride (banned by the FDA subsequent to the vote)
- Sodium dichloroacetate
- DMPS (approved but limited to IV in-hospital use)
- Methylsulfonylmethane (MSM)
- Germanium sesquioxide (already on the FDA’s Category 2 list of substances that can’t be compounded due to safety concerns)
- Rubidium chloride
Of note, Paul Anderson, ND, testified before the PCAC in support of sodium dichloroacetate, stating that his group had administered over 10,000 doses orally and IV as an adjunct treatment for cancer. Anderson testified at the same committee meeting in favor of cesium chloride. Both substances were voted down unanimously by the PCAC and cesium chloride was ultimately banned by the FDA.
Although the PCAC’s vote is not dispositive, this does not bode well for the naturopaths and like-minded practitioners, or their wallets. Thus, the AANP has initiated a campaign to “save” compounded medications, including a GoFundMe campaign.
The AANP misleadingly cites medically accepted uses of compounded medications (e.g., allergies to ingredients, different dosing requirements) as reasons to object to the FDA’s action, conveniently eliding the fact that experts are rejecting their nominations because they lack evidence of efficacy and safety or are known to be inefficacious or unsafe. In fact, the reasons the AANP cites normally apply only to substances that have been through the FDA drug approval process, not random ingredients naturopaths use to concoct their compounded remedies. These inconvenient truths would reveal to their patients the fact that naturopaths want prescribe and administer drugs that couldn’t even make it through a review far less rigorous than FDA-approved prescription drugs.
As part of its campaign, the AANP filed a Citizens Petition on behalf of itself and the American Academy of Environmental Medicine, American College or Advancement in Medicine, American College of Integrative Medicine, and Academy of Integrative Health and Medicine (whose mostly online “fellowship” program allows participants to become board certified in “Integrative Medicine”), along with two compounding pharmacies. (Note that you can comment on the Petition.)
They also plan to “ask Congress to pass a bill to stop FDA’s overreach”, apparently with some success. A bill has been introduced that will, according to the Alliance for Natural Health, (an organization that promotes your “right” to pseudoscientific treatments) allow some dietary supplements to be automatically included among approved substances for compounding. (The actual text is not yet available on congress.gov.)
Although the FDA’s process is painfully slow, the agency’s renewed interest in traditional compounding is an important step in curbing the abuse of patients by naturopaths and other fringe practitioners. A fortunate side effect is the creation of a record, through nominations of substances for the 503A Bulks List and testimony and other evidence presented to the PCAC, exposing just how steeply entrenched in pseudoscience naturopaths are and how little regard they have for the health and safety of their patients. It’s like “What naturopaths say to each other when they think no one’s listening” (also here): a transcript of their pseudoscientific thinking plus expert evaluation of their claims, but all on the public record. It’s a target-rich environment, and one whose revelations I hope to pursue further in a future post.