Friday, 16 February 2018

US Regulation of Homeopathy #1 - Manufacture etc

US regulation of homeopathic medicines and the practice of homeopathy is complicated to say the least. Part of the reason is the nature of the US law system and issues of demarcation of jurisdiction of regulatory bodies. This is a very complicated subject and well beyond the scope of this blog!

Suffice to say, there is Federal law and State law. Regulation of some aspects of the manufacture of homeopathic medicines is at the Federal level but licensing of manufacturers and wholesalers is often at state level, regulation of marketing claims for homeopathic medicines is at both the Federal and State level and the regulation of the practice of homeopathy is at State level. The latter is complicated by the fact that "homeopathy" as a practice is comparatively rare. It is more commonly encountered as one of types of treatment employed in naturopathy. The regulatory status of naturopathy varies considerably from state to state. The number of states makes this a huge exercise.

At the Federal level, in general the Food and Drug Administration (FDA)  is responsible for regulation of the manufacturing side of homeopathic drugs. It also deals with the placing on the market of those homeopathic drugs that are prescription only (see below). The Federal Trade Commission (FTC) deals with the marketing of over the counter products. It is not intended to go into detail explaining their function or powers.

Over the past year or so, there have been a number events, mostly at the Federal level, that could have big impacts on the market for homeopathic medicines.

How many posts it will take to cover the whole subject is unknown but it will likely be more than three and they will not be short. Nor will they be an easy read. No apologies are made for this.

The Federal Food Drug and Cosmetic Act
The FDCA is a complex piece of legislation. It has a long history and has been subject to many amendments over the years. It is necessarily large as it attempts to do in one Act what other jurisdictions tend to split across multiple pieces of legislation. It is also not structured in a particularly structured fashion.

It is worth pointing out that the status of homeopathic drugs has never been particularly clear. This excellent article written by the FDA's official historian clearly demonstrates this. 

Definition
It provides a definition of a "drug" in Section 321
(g)(1) The term "drug" means (A) articles recognized in the official United States Pharmacopoeia, official Homoeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to any of them; and (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and (C) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and (D) articles intended for use as a component of any article specified in clause (A), (B), or (C). A food or dietary supplement for which a claim, subject to sections 343(r)(1)(B) and 343(r)(3) of this title or sections 343(r)(1)(B) and 343(r)(5)(D) of this title, is made in accordance with the requirements of section 343(r) of this title is not a drug solely because the label or the labeling contains such a claim. A food, dietary ingredient, or dietary supplement for which a truthful and not misleading statement is made in accordance with section 343(r)(6) of this title is not a drug under clause (C) solely because the label or the labeling contains such a statement.
So, a "drug" is essentially a drug because it appears in a list of drugs OR if not, 
  • it is intended for use of diagnois, cure, mitigation, treatment or prevention of disesase in man or animals OR
  • it is intended to affect the structure or function of the body
Or is an ingredient of any of the above. Food items are not drugs. Nor are "dietary supplements". Dietary supplements will be dealt with later.
(j) The term "official compendium" means the official United States Pharmacopoeia, official Homoeopathic Pharmacopoeia of the United States, official National Formulary, or any supplement to any of them.
Does not add anything. 

The FDCA does not provide an explicit definition of "homeopathic". The implication is that if a monograph of a substance appears in the Homoeopathic Pharmacopoeia of the United States (HPUS), it is considered homepathic. HPUS will be discussed in great depth later but this is very different from, say, the EU definition of a "homeopathic medicine". EU regulations are methods based for one thing. It is partly the process by which a product is prepared that determines whether it homeopathic. Another part of EU regulations is the degree of dilution - which simply does not exist in the FDCA.

The FDA have produced consumer guidance on homeopathic drugs. It gives a brief and very partial explanation of what homeopathy is but in the section "What are homeopathic products and how can you tell you are taking one?" it states -
There are no FDA-approved products labeled as homeopathic; this means that any product labeled as homeopathic is being marketed in the U.S. without FDA evaluation for safety or effectiveness. These products are often marketed as natural, safe and effective alternatives to approved prescription and nonprescription products, and are sold online and in major retail stores. 
Products labeled as homeopathic can contain a wide range of substances, including ingredients derived from plants, healthy or diseased animal or human sources, minerals, and chemicals. 
Products labeled as homeopathic generally include:
  • The word “Homeopathic”
  • The ingredients listed in terms of dilution, e.g. 1X, 6X, 2C
Which is not very helpful.

The FDA's current Compliance Guidelines - CPG Sec. 400.400 Conditions Under Which Homeopathic Drugs May be Marketed - can be found here. Note that compliance guidelines in themselves do not represent the law itself but rather what the FDA thinks is necessary to comply with law. Enforcement guidelines are something different - they represent FDA enforcement priorities. The FDCA does not de facto treat homeopathic drugs any differently from other drugs - the FDA chooses not to enforce the letter of the law in some cases.

Although CPG Sec. 400.400 does not have force of law it states -
Homeopathic Drug: Any drug labeled as being homeopathic which is listed in the Homeopathic Pharmacopeia of the United States (HPUS), an addendum to it, or its supplements. The potencies of homeopathic drugs are specified in terms of dilution, i.e., 1x (1/10 dilution), 2x (1/100 dilution), etc. Homeopathic drug products must contain diluents commonly used in homeopathic pharmaceutics. Drug products containing homeopathic ingredients in combination with non-homeopathic active ingredients are not homeopathic drug products.
Again, the reliance on HPUS. If a homeopathic drug contains any ingredients that are not in HPUS, at the moment the FDA would not regard them as homeopathic. This is true even when ingredients are listed as "inactive". 

Homoeopathic Pharmacopoeia of the United States
The HPUS website is here. It is a very strange thing to say the least. That what is essentially a reference work that defines a group of drugs under Federal law is under the control of a non-statutory body is odd.
The Homœopathic Pharmacopœia Convention of the United States is an all-volunteer organization that is funded through member dues, subscriptions and charitable giving. HPCUS is a 501(c)3 corporation, and as such all donations are deductible for tax purposes. Thank you for your support of the HPCUS!
Access to what is contained in HPUS costs money. This makes it impossible for consumers to determine whether homeopathic drugs are "homeopathic" or not. Criteria for inclusion in HPUS can be found here. The criteria mention efficacy - but obviously this has a different meaning than the dictionary definition. They also mention safety.

One of the strange aspects of the HPUS is that classifies some products as prescription only when the FDCA does not recognise any distinction between homeopathic drugs as long as they are in HPUS.

Manufacturing - Registration of producers and inspection
The FDCA starts to become confusing at this point. It certainly doesn't flow - as will be seen from the out of order numbered sections.

Section 360 - Registration of producers of drugs or devices is very clear.

(a) Definitions
As used in this section-
(1) the term "manufacture, preparation, propagation, compounding, or processing" shall include repackaging or otherwise changing the container, wrapper, or labeling of any drug package or device package in furtherance of the distribution of the drug or device from the original place of manufacture to the person who makes final delivery or sale to the ultimate consumer or user; and
(2) the term "name" shall include in the case of a partnership the name of each partner and, in the case of a corporation, the name of each corporate officer and director, and the State of incorporation.

The section then goes on to describe in detail - 
  • For already registered producers, the need renew their registration on an annual basis.
  • The need for new producers to register.
  • The need for additional premises to be registered
  • The issue of unique ID numbers
  • Registration details are available to any one.
It then talks about exclusions from registration -

(g) Exclusions from application of sectionThe foregoing subsections of this section shall not apply to-(1) pharmacies which maintain establishments in conformance with any applicable local laws regulating the practice of pharmacy and medicine and which are regularly engaged in dispensing prescription drugs or devices, upon prescriptions of practitioners licensed to administer such drugs or devices to patients under the care of such practitioners in the course of their professional practice, and which do not manufacture, prepare, propagate, compound, or process drugs or devices for sale other than in the regular course of their business of dispensing or selling drugs or devices at retail;(2) practitioners licensed by law to prescribe or administer drugs or devices and who manufacture, prepare, propagate, compound, or process drugs or devices solely for use in the course of their professional practice;(3) persons who manufacture, prepare, propagate, compound, or process drugs or devices solely for use in research, teaching, or chemical analysis and not for sale;(4) any distributor who acts as a wholesale distributor of devices, and who does not manufacture, repackage, process, or relabel a device; or(5) such other classes of persons as the Secretary may by regulation exempt from the application of this section upon a finding that registration by such classes of persons in accordance with this section is not necessary for the protection of the public health.

Compounding pharmacies were mentioned in a previous post and that post linked to this article. In essence, compounding pharmacies are permitted to formulate medicines in response to a prescription from a licensed medical practitioner. Placing drugs on the open market is not permitted. Compounding pharmacies are subject to State regulation. (2) and (3) also forbid the placing on the market. The degree of abuse of exemptions is unknown but sufficient that FDA that felt it had to act.

It then goes onto discuss inspections. It sets out a risk-based approach to the frequency and scheduling of inspections. Section 374 - Inspection discusses the nature of these inspections, the powers of inspecting agents, the potential outcomes of such inspections (eg improvement notices) and various exemptions. Inspections are carried out on the basis of compliance with current Good Manufacturing Practice (cGMP).


(i) Registration of foreign establishments
(1) Every person who owns or operates any establishment within any foreign country engaged in the manufacture, preparation, propagation, compounding, or processing of a drug or device that is imported or offered for import into the United States shall, through electronic means in accordance with the criteria of the Secretary-(A) upon first engaging in any such activity, immediately submit a registration to the Secretary that includes-(i) with respect to drugs, the name and place of business of such person, all such establishments, the unique facility identifier of each such establishment, a point of contact e-mail address, the name of the United States agent of each such establishment, the name of each importer of such drug in the United States that is known to the establishment, and the name of each person who imports or offers for import such drug to the United States for purposes of importation; and(ii) with respect to devices, the name and place of business of the establishment, the name of the United States agent for the establishment, the name of each importer of such device in the United States that is known to the establishment, and the name of each person who imports or offers for import such device to the United States for purposes of importation; and(B) each establishment subject to the requirements of subparagraph (A) shall thereafter register with the Secretary during the period beginning on October 1 and ending on December 31 of each year.(2) The establishment shall also provide the information required by subsection (j).(3) The Secretary is authorized to enter into cooperative arrangements with officials of foreign countries to ensure that adequate and effective means are available for purposes of determining, from time to time, whether drugs or devices manufactured, prepared, propagated, compounded, or processed by an establishment described in paragraph (1), if imported or offered for import into the United States, shall be refused admission on any of the grounds set forth in section 381(a) of this title.(4) The Secretary shall specify the unique facility identifier system that shall be used by registrants under paragraph (1) with respect to drugs. The requirement to include a unique facility identifier in a registration under paragraph (1) with respect to drugs shall not apply until the date that the identifier system is specified by the Secretary under the preceding sentence.
This requires foreign producers to register and also makes them subject to inspection.
(j) Filing of lists of drugs and devices manufactured, prepared, propagated and compounded by registrants; statements; accompanying disclosures
(1) Every person who registers with the Secretary under subsection (b), (c), (d), or (i) shall, at the time of registration under any such subsection, file with the Secretary a list of all drugs and a list of all devices and a brief statement of the basis for believing that each device included in the list is a device rather than a drug (with each drug and device in each list listed by its established name (as defined in section 352(e) of this title) and by any proprietary name) which are being manufactured, prepared, propagated, compounded, or processed by him for commercial distribution and which he has not included in any list of drugs or devices filed by him with the Secretary under this paragraph or paragraph (2) before such time of registration. Such list shall be prepared in such form and manner as the Secretary may prescribe and shall be accompanied by-(A) in the case of a drug contained in the applicable list and subject to section 355 or 360b of this title, or a device intended for human use contained in the applicable list with respect to which a performance standard has been established under section 360d of this title or which is subject to section 360e of this title, a reference to the authority for the marketing of such drug or device and a copy of all labeling for such drug or device;(B) in the case of any other drug or device contained in an applicable list-(i) which drug is subject to section 353(b)(1) of this title, or which device is a restricted device, a copy of all labeling for such drug or device, a representative sampling of advertisements for such drug or device, and, upon request made by the Secretary for good cause, a copy of all advertisements for a particular drug product or device, or(ii) which drug is not subject to section 353(b)(1) of this title or which device is not a restricted device, the label and package insert for such drug or device and a representative sampling of any other labeling for such drug or device;(C) in the case of any drug contained in an applicable list which is described in subparagraph (B), a quantitative listing of its active ingredient or ingredients, except that with respect to a particular drug product the Secretary may require the submission of a quantitative listing of all ingredients if he finds that such submission is necessary to carry out the purposes of this chapter;(D) if the registrant filing a list has determined that a particular drug product or device contained in such list is not subject to section 355 or 360b of this title, or the particular device contained in such list is not subject to a performance standard established under section 360d of this title or to section 360e of this title or is not a restricted device a brief statement of the basis upon which the registrant made such determination if the Secretary requests such a statement with respect to that particular drug product or device; and(E) in the case of a drug contained in the applicable list, the name and place of business of each manufacturer of an excipient of the listed drug with which the person listing the drug conducts business, including all establishments used in the production of such excipient, the unique facility identifier of each such establishment, and a point of contact e-mail address for each such excipient manufacturer.(2) Each person who registers with the Secretary under this section shall report to the Secretary, with regard to drugs once during the month of June of each year and once during the month of December of each year, and with regard to devices once each year during the period beginning on October 1 and ending on December 31, the following information:(A) A list of each drug or device introduced by the registrant for commercial distribution which has not been included in any list previously filed by him with the Secretary under this subparagraph or paragraph (1) of this subsection. A list under this subparagraph shall list a drug or device by its established name (as defined in section 352(e) of this title), and by any proprietary name it may have and shall be accompanied by the other information required by paragraph (1).(B) If since the date the registrant last made a report under this paragraph (or if he has not made a report under this paragraph, since February 1, 1973) he has discontinued the manufacture, preparation, propagation, compounding, or processing for commercial distribution of a drug or device included in a list filed by him under subparagraph (A) or paragraph (1); notice of such discontinuance, the date of such discontinuance, and the identity (by established name (as defined in section 352(e) of this title) and by any proprietary name) of such drug or device.(C) If since the date the registrant reported pursuant to subparagraph (B) a notice of discontinuance he has resumed the manufacture, preparation, propagation, compounding, or processing for commercial distribution of the drug or device with respect to which such notice of discontinuance was reported; notice of such resumption, the date of such resumption, the identity of such drug or device (each by established name (as defined in section 352(e) of this title) and by any proprietary name), and the other information required by paragraph (1), unless the registrant has previously reported such resumption to the Secretary pursuant to this subparagraph.(D) Any material change in any information previously submitted pursuant to this paragraph or paragraph (1).(3) The Secretary may also require each registrant under this section to submit a list of each drug product which (A) the registrant is manufacturing, preparing, propagating, compounding, or processing for commercial distribution, and (B) contains a particular ingredient. The Secretary may not require the submission of such a list unless he has made a finding that the submission of such a list is necessary to carry out the purposes of this chapter.(4) The Secretary shall require persons subject to this subsection to use, for purposes of this subsection, the unique facility identifier systems specified under subsections (b)(3) and (i)(4) with respect to drugs. Such requirement shall not apply until the date that the identifier system under subsection (b)(3) or (i)(4), as applicable, is specified by the Secretary.
A lot of words to state that registered producers must provide a list of drugs/devices and supporting documentation.

Towards the end of the section are a number of declarations that cite interstate commerce. This is an odd concept to those who do not live in US or other countries with a Federal system of goverment. To a degree, it sets limits on Federal jurisdiction - if acts occur purely within a State, they fall under its jurisdiction. If products and services cross State borders, they fall under Federal jurisdiction. This is gross over-simplification. It is also the case that in these days of effective distribution networks and mail order purchase via the internet that any infractions will fall under Federal jurisdiction.

The situation is complicated slightly by the fact that some States do implement the FDCA in their own legislation. Other states have similar legislation that covers much of what the FDCA does but differently worded, partial or with a particular emphasis. For example, the focus may on food. Again, an over-simplification.

New Drug
The FDA do not require homeopathic drugs to go through the New Drug Application (NDA) process. This can be subject to abuse. The legal requirements are long and complex and can be found in Section 355 - New drugs and the following sub-sections. There is also copious guidance.

No homeopathic drug of sufficient dilution would make it through the NDA process. If a product could make it through the process then it would not be regarded as homeopathic. 


Over the counter and Prescription drugs
Unlike some other countries, the US only has two categories of drugs. It does not have the equivalent of the UK Phamacy Only Medicine (POM) - which do not require a prescription but can only be purchased from a pharmacy. Over the counter (OTC) drugs - which corresponds to the UK General Sales List (GSL - although OTC is often used in UK) and can be sold anywhere and Prescription only (Rx) which can only be obtained from a pharmacy in conjunction with a prescription from a licensed medical professional with the appropriate prescribing rights. However, some States have laws that effectively render some OTC the equivalent of the UK POM. Also, although there is no legal requirement, some pharmacies de facto treat some OTC drugs in this way. 

The criteria for determing whether a drug is OTC or Rx are not set in stone. When an NDA (or an application for a change in status from Rx to OTC) for an OTC drug is made it is evaluated by FDA. The ultimate decision on OTC status is made by the Office of Nonprescription Drug Products.
OTC drugs generally have these characteristics:
  • their benefits outweigh their risks
  • the potential for misuse and abuse is low
  • consumer can use them for self-diagnosed conditions
  • they can be adequately labeled
  • health practitioners are not needed for the safe and effective use of the product
Homeopathic drugs would appear to fail to meet several criteria - they have no benefits and effective use is not possible yet they are treated as OTC. They are not evaluated by the Office of Nonprescription Drug Products.

In some jurisdictions, method of delivery affects OTC/Rx status - eg drugs for delivery by injection are considered Rx. Homeopathic drugs typically come in the form of lactose pillules although some for topical use come in the form of creams or gels (which may have a soothing effect for some conditions). Ear and eye drops do exist. As do transdermal patches and even inhalers of a kind. Suppositories too.

As mentioned above HPUS does make a distinction between OTC and Rx but this is not reflected in the FDCA. It is unknown whether HPUS recognises novel routes of delivery.

Restricted Ingredients
Although there are no specific prohibitions on what ingredients homeopathic can contain in FDCA per se, the Controlled Substances Act, for example, would make it legally difficult for manufacturers to obtain certain ingredients. Many controlled substances are relatively new so they will not appear in HPUS but older products such as Opium and some other opiates do.

Because of the lack of restrictions on dilution, products such as Opium 1x are in theory possible but would be subject to the CSA. 

Adulterated and Misbranded Drugs
These terms are not used in the same way as the dictionary definitions. They have broader and yet specific meanings.

Section 351 - Adultered drugs and devices states -
A drug or device shall be deemed to be adulterated— 
(a) Poisonous, insanitary, etc., ingredients; adequate controls in manufacture(1) If it consists in whole or in part of any filthy, putrid, or decomposed substance; or (2)(A) if it has been prepared, packed, or held under insanitary conditions whereby it may have been contaminated with filth, or whereby it may have been rendered injurious to health; or (B) if it is a drug and the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this chapter as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess; or (C) if it is a compounded positron emission tomography drug and the methods used in, or the facilities and controls used for, its compounding, processing, packing, or holding do not conform to or are not operated or administered in conformity with the positron emission tomography compounding standards and the official monographs of the United States Pharmacopoeia to assure that such drug meets the requirements of this chapter as to safety and has the identity and strength, and meets the quality and purity characteristics, that it purports or is represented to possess; or (3) if its container is composed, in whole or in part, of any poisonous or deleterious substance which may render the contents injurious to health; or (4) if (A) it bears or contains, for purposes of coloring only, a color additive which is unsafe within the meaning of section 379e(a) of this title, or (B) it is a color additive the intended use of which in or on drugs or devices is for purposes of coloring only and is unsafe within the meaning of section 379e(a) of this title; or (5) if it is a new animal drug which is unsafe within the meaning of section 360b of this title; or (6) if it is an animal feed bearing or containing a new animal drug, and such animal feed is unsafe within the meaning of section 360b of this title.
This would seem to indicate that nosodes and sarcodes would be considered "adultered drugs" as they are made from all sorts of unpleasant things. Excrement, pus and diseased tissue to name a few. More importantly, products are considered adultered if not manufactured to current Good Manufacturing Practice (cGMP) standards.
(b) Strength, quality, or purity differing from official compendium
If it purports to be or is represented as a drug the name of which is recognized in an official compendium, and its strength differs from, or its quality or purity falls below, the standard set forth in such compendium. Such determination as to strength, quality, or purity shall be made in accordance with the tests or methods of assay set forth in such compendium, except that whenever tests or methods of assay have not been prescribed in such compendium, or such tests or methods of assay as are prescribed are, in the judgment of the Secretary, insufficient for the making of such determination, the Secretary shall bring such fact to the attention of the appropriate body charged with the revision of such compendium, and if such body fails within a reasonable time to prescribe tests or methods of assay which, in the judgment of the Secretary, are sufficient for purposes of this paragraph, then the Secretary shall promulgate regulations prescribing appropriate tests or methods of assay in accordance with which such determination as to strength, quality, or purity shall be made. No drug defined in an official compendium shall be deemed to be adulterated under this paragraph because it differs from the standard of strength, quality, or purity therefor set forth in such compendium, if its difference in strength, quality, or purity from such standard is plainly stated on its label. Whenever a drug is recognized in both the United States Pharmacopoeia and the Homoeopathic Pharmacopoeia of the United States it shall be subject to the requirements of the United States Pharmacopoeia unless it is labeled and offered for sale as a homoeopathic drug, in which case it shall be subject to the provisions of the Homoeopathic Pharmacopoeia of the United States and not to those of the United States Pharmacopoeia.
This has implications for "homeopathic" drugs of low dilution that would be treated differently other jurisdictions.
(j) Delayed, denied, or limited inspection; refusal to permit entry or inspection
If it is a drug or device and it has been manufactured, processed, packed, or held in any factory, warehouse, or establishment and the owner, operator, or agent of such factory, warehouse, or establishment delays, denies, or limits an inspection, or refuses to permit entry or inspection.
In essence, if cGMP inspection is unable to be carried out, a drug can be declared "adultered".

Section 352 - Misbranded drugs and devices states -
A drug or device shall be deemed to be misbranded- 
(a) False or misleading label
(1) If its labeling is false or misleading in any particular. Health care economic information provided to a payor, formulary committee, or other similar entity with knowledge and expertise in the area of health care economic analysis, carrying out its responsibilities for the selection of drugs for coverage or reimbursement, shall not be considered to be false or misleading under this paragraph if the health care economic information relates to an indication approved under section 355 of this title or under section 262(a) of title 42 for such drug, is based on competent and reliable scientific evidence, and includes, where applicable, a conspicuous and prominent statement describing any material differences between the health care economic information and the labeling approved for the drug under section 355 of this title or under section 262 of title 42. The requirements set forth in section 355(a) of this title or in subsections (a) and (k) of section 262 of title 42 shall not apply to health care economic information provided to such a payor, committee, or entity in accordance with this paragraph. Information that is relevant to the substantiation of the health care economic information presented pursuant to this paragraph shall be made available to the Secretary upon request.
Only the first sentence of (a) is of potential relevance.
(b) Package form; contents of label 
If in package form unless it bears a label containing (1) the name and place of business of the manufacturer, packer, or distributor; and (2) an accurate statement of the quantity of the contents in terms of weight, measure, or numerical count: Provided, That under clause (2) of this paragraph reasonable variations shall be permitted, and exemptions as to small packages shall be established, by regulations prescribed by the Secretary. 

(c) Prominence of information on label  
If any word, statement, or other information required by or under authority of this chapter to appear on the label or labeling is not prominently placed thereon with such conspicuousness (as compared with other words, statements, designs, or devices, in the labeling) and in such terms as to render it likely to be read and understood by the ordinary individual under customary conditions of purchase and use.
Although general provisions, they equally apply to homeopathic drugs.
(f) Directions for use and warnings on label
Unless its labeling bears (1) adequate directions for use; and (2) such adequate warnings against use in those pathological conditions or by children where its use may be dangerous to health, or against unsafe dosage or methods or duration of administration or application, in such manner and form, as are necessary for the protection of users, except that where any requirement of clause (1) of this paragraph, as applied to any drug or device, is not necessary for the protection of the public health, the Secretary shall promulgate regulations exempting such drug or device from such requirement. Required labeling for prescription devices intended for use in health care facilities or by a health care professional and required labeling for in vitro diagnostic devices intended for use by health care professionals or in blood establishments may be made available solely by electronic means, provided that the labeling complies with all applicable requirements of law, and that the manufacturer affords such users the opportunity to request the labeling in paper form, and after such request, promptly provides the requested information without additional cost. 
A drug is misbranded if it does not carry direction for use or adequate warnings. 
(g) Representations as recognized drug; packing and labeling; inconsistent requirements for designation of drug
If it purports to be a drug the name of which is recognized in an official compendium, unless it is packaged and labeled as prescribed therein. The method of packing may be modified with the consent of the Secretary. Whenever a drug is recognized in both the United States Pharmacopoeia and the Homoeopathic Pharmacopoeia of the United States, it shall be subject to the requirements of the United States Pharmacopoeia with respect to packaging and labeling unless it is labeled and offered for sale as a homoeopathic drug, in which case it shall be subject to the provisions of the Homoeopathic Pharmacopoeia of the United States, and not those of the United States Pharmacopoeia, except that in the event of inconsistency between the requirements of this paragraph and those of paragraph (e) as to the name by which the drug or its ingredients shall be designated, the requirements of paragraph (e) shall prevail.
Not particularly interesting.
(i) Drug; misleading container; imitation; offer for sale under another name
(1) If it is a drug and its container is so made, formed, or filled as to be misleading; or (2) if it is an imitation of another drug; or (3) if it is offered for sale under the name of another drug.
This has particular implications for homeopathic drugs that purport to be equivalent in action to actual drugs - the most infamous example being "HCG Drops". These will be discussed in greater depth later.
(o) Drugs or devices from nonregistered establishments 
If it was manufactured, prepared, propagated, compounded, or processed in an establishment not duly registered under section 360 of this title, if it is a drug and was imported or offered for import by a commercial importer of drugs not duly registered under section 381(s) of this title, if it was not included in a list required by section 360(j) of this title, if a notice or other information respecting it was not provided as required by such section or section 360(k) of this title, or if it does not bear such symbols from the uniform system for identification of devices prescribed under section 360(e) of this title as the Secretary by regulation requires.
This seems a very indirect way to make the sale of homeopathic drugs manufactured in nonregistered facilities illegal.

Pharmacovigilence
Adverse drug reactions (ADRs) do happen. Most countries do have systems for the reporting of ADRs. Consumers may not be aware that regulatory bodies have schemes in place and sometimes will report ADRs to the manufacturer. The FDCA places a legal duty on manufacturers to pass ADRs on to the FDA.

There are problems with ADRs in that, generally, causation of an individual reaction are not known. Regulatory bodies therefore tend to look for patterns in ADRs for individual products. Frequency and/or severity of ADRs are what prompt regulators to carry out investigatory actions. If a drug is not commonly used and/or ADRs are rare (but severe) it can take time for sufficient data to accumulate.

The idea that homeopathic drugs do not have side effects may be a barrier to consumer reporting of ADRs. Of course, products of sufficient dilution correctly manufactured, are extremely unlike to cause ADRs but as discussed, some products are of low dilution. There is also the problem of contamination. The FDCA treat this as "adulteration".


Offenses and Penalties
The FDCA provides for a number of civil and criminal offences and sanctions against adultered drugs. Something that needs to be understood is that FDCA works on the principle of strict liability - ignorance of the law is no defence. 

Section 331 - Prohibited Acts states -


The following acts and the causing thereof are prohibited:
(a) The introduction or delivery for introduction into interstate commerce of any food, drug, device, tobacco product, or cosmetic that is adulterated or misbranded.(b) The adulteration or misbranding of any food, drug, device, tobacco product, or cosmetic in interstate commerce.(c) The receipt in interstate commerce of any food, drug, device, tobacco product, or cosmetic that is adulterated or misbranded, and the delivery or proffered delivery thereof for pay or otherwise.(d) The introduction or delivery for introduction into interstate commerce of any article in violation of section 344, 350d, 355, or 360bbb–3 of this title.(e) The refusal to permit access to or copying of any record as required by section 350a, 350c, 350f(j), 350e, 354, 360bbb–3, 373, 374(a), 379aa, or 379aa–1 of this title; or the failure to establish or maintain any record, or make any report, required under section 350a, 350c(b), 350f, 350e, 354, 355(i) or (k), 360b(a)(4)(C), 360b(j), (l) or (m), 360ccc–1(i), 360e(f), 360i, 360bbb–3, 379aa, 379aa–1, 387i, or 387t of this title or the refusal to permit access to or verification or copying of any such required record; or the violation of any recordkeeping requirement under section 2223 1 of this title (except when such violation is committed by a farm).(f) The refusal to permit entry or inspection as authorized by section 374 of this title.(g) The manufacture within any Territory of any food, drug, device, tobacco product, or cosmetic that is adulterated or misbranded.(h) The giving of a guaranty or undertaking referred to in section 333(c)(2) of this title, which guaranty or undertaking is false, except by a person who relied upon a guaranty or undertaking to the same effect signed by, and containing the name and address of, the person residing in the United States from whom he received in good faith the food, drug, device, tobacco product, or cosmetic; or the giving of a guaranty or undertaking referred to in section 333(c)(3) of this title, which guaranty or undertaking is false.
This clearly prohibits activities associated with manufacture, distribution and sale of adultered or misbranding drugs. It also prohibits refusal to allow inspection. It then goes on to talk about counterfiet drugs, various acts associated with margerine and tobacco. "Causing" in the context of this section has the meaning of instructing others to perform such acts.

Whilst the following Sections 332 - Injunctions and 333 - Penalties are important, they omit other sanctions open to the FDA. This, although it comes from part of the FDA website dealing with veterinary products, is very clear. The options opened to the FDA are -
Warning Letters - are sent to the individuals or firms, advising them of specific noted violations.; These letters request a written response as to the steps which will be taken to correct the violation. These letters constitute one form of warning that can be issued under current Agency policy. 
Seizure - An action brought against an FDA-regulated product because it is adulterated and/or misbranded within the meaning of the Act. The purpose of such an action is to remove specific violative goods from commerce. 
Injunction - An order by a court that requires an individual or corporation to do or refrain from doing a specific act. FDA may seek injunctions against individuals and/or corporations to prevent them from violating or causing violations of the Act. 
Criminal prosecution - may be recommended in appropriate cases for violation of Section 301 of the Act.; Misdemeanor convictions, which do not require proof of intent to violate the Act, can result in fines and/or imprisonment up to one year. Felony convictions, which apply in the case of a second violation or intent to defraud or mislead, can result in fines and/or imprisonment up to three years.
In the case of criminal prosecution, fines can be levied -
  • Up to $100,000 for a misdemeanor by an individual that does not result in death.
  • Up to $200,000 for a misdemeanor by a corporation that does not result in death.
  • Up to $250,000 for a misdemeanor by an individual that results in death, or a felony.
  • Up to $500,000 for a misdemeanor by a corporation that results in death, or a felony.
In all cases, a maximum of one year imprisonment is also possible.

Supplements
Homeopathic drugs are not supplements. Supplements are regulated as food to a large degree. To say the status of supplements is controversial is an understatement. The Dietary Supplement Health and Education Act of 1994 (DSHEA) defines supplements -

The term 'dietary supplement'— "(1) means a product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredients:(A) a vitamin; (B) a mineral; (C) an herb or other botanical; (D) an amino acid; (E) a dietary substance for use by man to supplement the diet by increasing the total dietary intake; or(F) a concentrate, metabolite, constituent, extract, or combination of any ingredient described in clause (A), (B), (C),(D),or(E);  

It then goes on to state that supplements can not contain certain substances (drugs etc), that they are not intended as food. The FDA regulate supplements with regards to cGMP compliance and adulteration and misbranding. This is too complex a subject to be discussed here.

What matters the most is terms of what claims are permitted for such products, the bar is set very low in terms of substantiation. Some products make claims that would be consistent with the FDCA definition of a drug but this is very grey area. 
Some homeopathic drugs are labelled as "homeopathic supplements". This is essentially meaningless and somewhat bogus. It may be done out of ignorance or it may be an attempt to avoid regulations (in particular the restriction to ingredients found in HPUS). Use of the term "homeopathic", use of dilution indicators etc, render a product a homeopathic drug. This is true for products described as dietary supplements or variations thereof.


Enforcement Actions
One way to determine what the FDA's approach to enforcement is by examining what enforcement actions have been taken and the which sections of the FDCA are cited. Typically, the FDA deals with infractions of the FDCA by warning letters and do not need to resort to prosecution. It is important to note that warning letters do not always contain an exhaustive list of infractions - the emphasis is on ensuring manufacturer/vendor compliance.

The most notorious example of problems with a "homeopathic" drug was the Zicam case although in other jurisdictions, Zicam would not be classified as such. The dilution levels are low and the product does contain significant levels of active ingredients - zinc acetate and zinc gluconate. Zicam caused anosmia - loss of sense of smell - in some consumers. the manufacturer Matrixx Initiatives was subject to a number of legal actions - some of which are still ongoing. In 2006, they settled with 340 customers for $12 million.

Cases of anosmia related to Zicam had been reported to the FDA from 1999 yet they only sent a warning letter to Matrixx Initiatives in 2009. The letter is no longer on the FDA website but it can be found here. The letter cites regulations relating new drugs and misbranding but also safety - the FDA state quite clearly that the product required approval that it did not have. Matrixx Initiatives were put under a great deal of pressure to recall the product. It was only in 2013 that the FDA closed out the case.

It is also the case that Matrixx Initiatives had received ADRs but did not pass them onto the FDA.

Less well known is the business of homeopathic hCG. This is a long story not all of which is in the public domain. Essentially there is a Very Low Calorie Diet (VLCD) that also involves the use of injections of human Chorionic Gonadotropin (hCG). It has been around since the 1950s. VLCDs are potentially dangerous and should only be conducted under medical supervision. hCG is Rx and licensed for treatment of female infertility. Any weight loss is due to the VLCD, not the hCG. Historically, the FDA have acted against those offering hCG for weight loss.

It is not clear who dreamed up the idea of homeopathic hCG. The idea that a dilution of hCG would have the same purported effect as hCG is nonsensical and violates the tenets of homeopathy. The marketing of these products represents a double lie. As hCG is not in HPUS, these products are not homeopathic drugs. The marketing of these products encouraged potentially dangerous behaviour - often not even mentioning the need for medical supervision. The products were sold by multiple internet vendors under various brands, even using Amazon and eBay. It is known that multiple complaints were made to the FDA. The FDA and FTC cooperated in enforcement actions. Warning letters were send to a number of vendors/manufacturers -
There were several other letters as well but they have proved difficult to track down but these letters provide more than enough information. Ignoring the FTC aspects of the letters (which will be discussed in a future post), the FDA stated that they considered the products new drugs. The FDA stated that disclaimers were meaningless and the marketing claims made meant that the products were drugs and Rx.

The FDA and FTC explicitly stating that homeopathic hCG products were illegal had a dramatic effect beyond these letters. Amazon and eBay would pull the products as soon as they were aware of them. If vendors used PayPal, they would suspend their accounts.

Some vendors changed the formulation of the products and the names changed but products still turn up from time to time. Nutri-Dyn Midwest, Inc had a warning letter in 2017. There are products still on the market and that website has this extraordinary page that brazenly violates both the FDCA and the FTC Act.

Another high profile case involves Hylands etc teething products. This was widely reported. These products contained belladonna, better known as deadly nightshade, which is a member of potato/tomato family. The plant is extremely toxic due to alkaloids such as atropine and hyoscine. The FDA has over the years recieved a number of ADRs related to the products  - including seizures.

The FDA carried out an inspection of Standard Homeopathic Products (parent company of the Hylands brand) in 2010. This inspection raised a number of issues. The FDA were concerned enough to issue a safety alert about teething products and advised consumers to dispose of them.

The FDA felt that Standard had not responded to the issues raised by the inspection and issued a warning letter in 2011. The letter cites numerous examples of cGMP non-compliance. The importance of cGMP compliance can not be overstated. The issue is not whether the products manufactured were safe or not but that there were inadequate controls to ensure safety. Put another way, safety became a matter of luck not judgement. Whilst the requirements of cGMP compliance are onerous, they are not impossible to acheive.

Then in 2013, the FDA looked at the Hylands website and found it contained a number of misbranded products. It issued a warning letter making it very clear that the marketing claims and indications for certain products were not permissable. This suggests that the FDA were keeping an eye on Standard.

In September 2016, the FDA inspected Standard and again found problems with belladonna products. Shortly afterwards, they issued a press release regarding belladonna teething products. The FDA also stated that there were analysing ADRs.

At roughly the same time, the FDA inspected Raritan and found problems with a similar product. Raritan launched a voluntary recall of the product in November 2016.

In January 2017 the FDA issued a laboratory report on belladona teething products marketed as Hylands and also CVS (manufacturered by Raritan). As the report makes clear, given the dilutions involved, these products should not have contained detectable levels of belladonna but they did. As a letter to Standard makes clear, Standard made no immediate attempt to recall the products. The letter is a formal request for Standard to issue a recall, which it finally did in April 2017.

The media became interested in the story at some point. Stories appeared even in the mainstream press - often couched in terms of as many as ten children having died as a result of being given these products. As mentioned earlier, ADRs do not always reveal causation.

The reactions of supporters of homeopathy varied. As might be expected, some painted the FDA actions as part of a conspiracy. Others stated that not all samples contained belladonna and those that did contained very little. Bizarre justifications were also made although the lines of those critical of homeopathy could not state that homeopathy is ineffective and that these products were potentially dangerous. Supporters seemed to fail to grasp that the issue was failure of process controls. Anyone familiar with statistical process control would tell you that.

GUNA, Inc and King Bio Inc have both been sent waring letters jointly issued by the FDA and the FTC as part of a clampdown on vendors offering products for the treatment of opioid addiction. Offering useless products in the climate of increasing problems with opioid addiction in the US can only be regarded as incredibly cynical. As above, the FTC element will be discussed in the next post. The Guna product would not be considered homeopathic in other jurisdictions as it is a combination product that contains several very low dilutions - but they are in HPUS. The FDA state that neither of these products are permitted on the basis that narcotic addiction is not amenable to self-treatment. The products would be considered Rx.

  


2 comments:

  1. A veritable tour de force. Thanks for doing that - very useful and interesting.

    ReplyDelete
  2. I agree with Zeno. That is a VERY COMPREHENSIVE resource. (As an aside, so THIS is why my Arcus Crepitu Unicornis cannot be considered a homeopathic medicine... Hmmm...)

    ReplyDelete