February 2018

Regulatory Radar: Homeopathic Drugs – FDA enhancing its Oversight

The practice of homeopathy is based on the belief that disease symptoms can be cured by small doses of substances that produce similar symptoms in healthy people. FDA has indicated that it intends to strengthen its regulatory oversight of certain homeopathic drugs. It will be reviewing products more closely, especially products that:

  • Have reported safety concerns
  • Are reported to contain non-Homoeopathic Pharmacopoeia Convention of the United States (HPUS) ingredients
  • Are administered in ways other than oral and topical
  • Promise to treat serious illnesses and life-threatening diseases rather than symptoms, and those aimed at vulnerable populations

In today’s market, homeopathic products are predominantly available as OTC drugs intended solely for self-limiting disease conditions amenable to self-diagnosis (of symptoms), whereas a homeopathic drug intended to treat the disease itself must be prescribed by licensed practitioners. However, there are no known prescription homeopathic drugs approved under an NDA.

The potency of homeopathic drugs is specified in terms of dilution or serial deconcentration of a substance, i.e., 1x or 1/10 dilution, 2x or 1/100 dilution, etc. Multiple dilutions of homeopathic drugs are based on two main principles that underlie homeopathy: the belief that a substance that causes symptoms in healthy subjects can be used in diluted form to treat symptoms and illnesses (known as “like-cures-like”) and that the more diluted the substance, the more potent it is (known as the “law of infinitesimals”). For example, red onion (Allium cepa) exposure can cause watery eyes and a runny nose in a healthy individual, so according to homeopathic theories, Allium cepa made from the red onion serially diluted may relieve seasonal allergy symptoms of runny eyes and nose.

Homeopathic drugs must comply with standards for strength, quality and purity set forth in the HPUS, meet labeling requirements and be manufactured under cGMPs. Indeed, the legal definition of a drug (21 U.S.C. 321(g)) includes articles recognized in the HPUS or any of its supplements. The current HPUS lists over 1,286 officially recognized products and in order for a product to be eligible for inclusion in the HPUS, the drug must meet at least the following three criteria:

  • The HPCUS (Homoeopathic Pharmacopoeia Convention of the United States) has determined that the drug is safe and effective.
  • The drug must be prepared according to the specifications of the General Pharmacy and relevant sections of the HPUS.
  • The submitted documentation must be in an approved format as set forth in the relevant sections of the Homoeopathic Pharmacopoeia of the United States.

In addition it needs to meet at least one of the following criteria:

  • The therapeutic use of a new and non-official homeopathic drug is established by a homeopathic drug proving and clinical verification acceptable to the HPCUS.
  • The therapeutic use of the drug is established through published documentation that the substance was in use prior to 1962.
  • The therapeutic use of the drug is established by at least two adequately controlled double blind clinical studies using the drug as the single intervention; the study is to be accompanied by adequate statistical analysis and adequate description of the symptom picture acceptable to the HPCUS which includes the subjective symptoms and, where appropriate, the objective symptomatology.
  • The therapeutic use of the drug is established by a) data gathered from clinical experience encompassing the symptom picture, pre- and post-treatment, including subjective and any available objective symptoms or b) data documented in the medical literature (all sources of medical literature may be considered on a case-by-case basis) subjected to further verification (statistical and/or other forms of verification).

In the past, the regulatory oversight of homeopathic drugs was spelled out in the FDA Compliance Guide (CPG) 400.4001 which has not been updated since 1988. In addition, where homeopathic OTC drugs are subject to FDA’s oversight of non-prescription drugs review for safety and efficacy, FDA has not used this authority. As such, the homeopathic drug market has expanded in the presence of minimal compliance oversight from the FDA.

This is changing with the issue of the new FDA draft guidance that, once finalized, will replace the out-of-date FDA compliance guide1 (CPG). The guide was drafted for many reasons including the increased use of homeopathic products which now represents a multi-billion dollar industry involving mass production, where in the past, these products were less common and mostly prepared by homeopathic physicians for individual patients. Other reasons that prompted FDA to enhance its oversight included findings of certain ingredients at excess and inconsistent levels in homeopathic products, specifically those marketed for use in children, and feedback from an April 2015 public hearing on the current use of homeopathic drugs and FDA’s role to best promote and protect the public health. For example, FDA has issued several warnings to consumers and recommended recalls of certain products regarding excess and inconsistent belladonna content in homeopathic teething tablets that posed an unnecessary risk to infants and children. Belladonna a plant-derived ingredient could cause seizures, excessive sleepiness, muscle weakness and skin flushing in children. In addition, FDA issued warning letters to specific homeopathic drug manufacturers whose products included the ingredient nux vomica, which contains highly toxic strychnine, a plant-derived neurotoxin that causes muscle spasms and respiratory failure that can lead to death; it is commonly used as a pesticide and rodenticide.

In the newly issued draft guidance, Drug Products Labeled as Homeopathic (December 2017), FDA formally lays out a risk-based approach for homeopathic products that pose a higher risk to the public.

In this guidance FDA identifies the following categories of drug products posing higher risk:

  • Products with reported safety concerns: Information available to the Agency (e.g. through MedWatch) that indicates or signals a potential correlation between the product and observed adverse events, medication error or other safety issues.
  • Products that contain or purport to contain ingredients associated with potentially significant safety concerns e.g. those claiming to contain:
    • Infectious agents that could be pathogenic
    • A controlled substance as defined by the Controlled Substances Act (21 U.S.C. 812)
    • Multiple ingredients that together could raise safety concerns due to interactions or synergistic or additive effects
    • Ingredients that pose potential toxic effects, particularly when those ingredients are concentrated or in low dilution presentations (e.g. 1X, 2X or 1C (1:100 dilution)) or are NOT adequately controlled in the manufacturing process (e.g. belladonna in teething tablets)
  • Products for routes of administration other than oral and topical, e.g. injectable drug products and ophthalmic drug products
  • Products intended to be used for the prevention or treatment of serious and/or life-threatening diseases and conditions (included as high risk in part given that they may delay users to delay or discontinue treatments that have found safe and effective through NDA/BLA approval process)
  • Products for vulnerable populations, e.g. immunocompromised individuals, the elderly, children and pregnant women
  • Products deemed to be adulterated under section 501 of the FD&C Act, e.g. significant violations of current GMPs or not meeting standards specified in an official compendium for strength, quality or purity

From the agency’s perspective, the identification of these risk categories will better direct its resources for compliance oversight by targeting homeopathic drug products that are most likely to present a public health risk. Manufacturers of homeopathic drugs will have to take a closer look at their processes and procedures as FDA warning letters issued to homeopathic drug manufacturers commonly cite cGMP violations and, in some cases, FDA strongly recommends that companies engage cGMP consultants.

Of course, a summary of the U.S. oversight of homeopathic medicines is not complete without mentioning the Federal Trade Commission’s (FTC) supervision of OTC advertising and its perspective on efficacy claims in advertisement to consumers. FDA has a requirement that homeopathic drugs display an indication for use, even when the product has not been demonstrated to be efficacious for that indication, which creates a potential conflict with the FTC’s requirement that health-related claims be substantiated by competent and reliable scientific evidence.

FTC held workshops to better understand the homeopathic industry and to address concerns that many consumers are likely being misled by current marketing claims. FTC recommended that the FDA consider three possible approaches: withdraw the FDA Compliance Guide (CPG), thereby subjecting homeopathic drugs to the same regulatory requirements as other drug products; eliminate the requirement in the CPG that an indication appear on labeling; or require that any indication appearing on the labeling be supported by competent and reliable scientific evidence.

The American Association of Homeopathic Pharmacists (AAHP) instead recommends a voluntary advertising and labeling disclaimer be provided as means of preventing consumer deception. Its proposal was based on the first sentence of the Dietary Supplement Health and Education Act (DSHEA) disclaimer adopted by Congress for dietary supplements, namely: “This statement has not been evaluated by the Food and Drug Administration.” A statement is already commonly used in the labeling and advertising of homeopathic drug products.

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1 See FDA Compliance Policy Guide 400.400, Conditions Under Which Homeopathic Drugs May be Marketed at https://www.fda.gov/ICECI/ComplianceManuals/CompliancePolicyGuidanceManual/ucm074360.htm