RAC US FRA Chapter 27

HPUS Approval Process

- A drug must have sufficient clinical data or "drug proving" to show efficacy. In a drug proving, a homeopathically prepared substance is administered to healthy volunteers in order to produce the symptoms specific to that substance and thereby reveal its inherent curative powers. The goal is to provoke temporary symptoms associated with the homeopathic medication. Symptoms are arranged to form a symptom pattern or remedy picture.To be eligible: · HPCUS has determined that the drug is safe and effective. · Drug must be prepared according to the specification of the General Pharmacy and relevant sections of HPUS · Documentation must be in an approved format. · Therapeutic use is established by one of 4 options.

Dietary Supplement Health and Education Act (1994)

- Enacted by Congress following public debate concerning the importance of dietary supplements in leading a healthy life, the need for consumers to have current and accurate information about supplements - DSHEA defined dietary supplement, dietary ingredient; required ingredient and nutritional labeling; provided for claims and nutritional support statements that can be used for dietary supplements; outlined guidelines for information that can be provided on supplement products and gave the FDA authority to establish Good Manufacturing Practices - Created a new class of FDA regulated product - Not subject to approval before marketing - Dietary supplement product labels must include a supplement facts box that is similar but not identical to the nutrition facts box used on food - Dietary ingredients not on the market prior to 1994 must be the subject of NDA petitions that are similar in content to "Generally Recognized as Safe" GRAS notifications used for food additives - Most content claims that were established with NLEA may be used on dietary supplement products - Prior to 1994 dietary supplements were regulated as foods

Nutrition Labeling Education Act (1990)

- Requiring FDA to regulate food labeling and include references to dietary supplements

Homeopathic Products

-Derived from the Greek words homeo (similar) and pathos (disease). Homeopathy is the practice of treating the syndromes and conditions constituting disease with remedies that have produced similar syndromes and conditions in healthy subjects. · 1906: Senator Royal Copeland amended the Food and Drugs Act of 1906 by defining "drug" to include those homeopathic drugs listed in the HPUS. Between 1938 - 1988, homeopathic drugs were sold in a regulatory vacuum. · Are a class of drug products regulated though a Compliance Policy Guide, CPG 7132.15 "Conditions under which homeopathic drugs may be marketed." Not subject to the NDA process. - FDA does not regulate homeopathic drugs in the same way as conventional drugs. Agency treats homeopathic drugs, both prescription and OTC quite differently. Homeopathic are not subject to premarket approval and are not subject to the FDA review process. They need to comply with a monograph.

Small Entity Compliance Guide (SECG)

-Stating in plain language the 21 CFR 211 requirements. · Dec 2010: FDA took add'l steps to keep consumers safe o A letter from the FDA commissioner to the dietary supp industry emphasizing its legal obligation to prevent tainted products from reaching US market. o New rapid public notification system (RSS Feed) on website to quickly warn consumers.

More Chapter 27 Answers

1. C 2. E 3. A 4. True 5. False - DSHEA of 1994 is the main governing regulation

Chapter 27 Answers

1. D 2. False. They do not apply. 3. D They must be labeled that it is intended for export. 4. A Responsible person must retain records related to each report for 6 years. 5. A Subject to the applicable FDA regulations for labeling, advertising and promotion.

Chapter 27 Questions:

1. Homeopathic drugs: a. Regulated in the same way as conventional drugs. b. Subject to premarket approval. c. Subject to the FDA review process. d. Need to comply with a monograph. 2. True or False - Dietary Supplement Good Manufacturing Practices do apply to retail establishments holding supplements only for purposes of direct retail sale to individual consumers. 3. Which one of the following statements is false regarding dietary supplements? a. Dietary supplements and dietary ingredients are regulated as foods by FDA b. FDA issues the "certificate of free sale" as an export certificate for food, including dietary supplements. c. Foreign facilities importing dietary supplements are required to designate a US agent for registering. d. Dietary supplements intended for foreign countries must be labeled that it is intended for import. 4. Which one of the following statements is false regarding dietary supplement adverse reporting? a. Responsible person must retain records related to each report for 10 years. b. Responsible person required to submit MedWatch Form 3500A along with a copy of the label. c. Submit no later than 15 business days. d. FDA requires mandatory reports be submitted in hard copy by mail only. 5. Which one of the following does not apply to the labeling of homeopathic products? a. Not subject to the applicable FDA regulations for labeling, advertising and promotion. b. Must comply with the provisions of Sections 502 and 503 of the FD& C Act and 21 CFR 201. c. Label shall contain "Homeopathic" in a prominent way. d. Include a statement of ingredients. e. The letters "HPUS" should be appended to the name of each official drug.

Dietary Supplement Good Manufacturing Practices

21 CFR 111 CGMP establishes the minimum of CGMPs necessary in manufacturing, packaging, labeling, or holding operations to ensure product quality for dietary supplements. Previously, manufactured under "umbrella" CGMPs established for food generally and not subject to individualized CGMPs · Dietary supplement CGMP rule went into effect 24 AUG 2007. FDA established compliance dates (2008-2010) that were tied to size of company and number of employees. · Applies to all domestic and foreign establishments that mfgr, package, label or hold dietary supplements. Does NOT apply to retail establishments holding supplements only for purposes of direct retail sale to individual consumers. Does NOT apply to dietary ingredient suppliers. · Requirements: procedures, cleaning (pest control), calibration, cleaning equipment, quality control operations, components, packaging, labels, lab operations, mfgring operations, packaging/labeling operations, holding and distribution requirements, returned dietary supps, and product complaints. · Outline: o Minimum requirements for personnel o Minimum requirements for physical plant and grounds, equipment, design and construction. o Establish specification in the production and process controls system. o Permit the use of a "COA" from a component supplier o Minimum requirements for representative samples o Minimum requirements for quality control o Preparation and use if a written master manufacturing record. o Require design and conduct of all manufacturing operations o Require testing of a subset of finished product batches o Establish minimum requirements for the batch production record o Require the establishment and use of lab control processes. o Minimum requirements for packaging and labeling operations. o Require reserve samples of supps to be held in a protected manner. o Holding of components and dietary supps under appropriate conditions o Minimum quality control operations for returned supps. o Qualified person to investigate any "product complaint" that involves a possible failure o Minimum requirements for records and recordkeeping o Records be kept for one year beyond the shelf lie or if no shelf life, two years beyong the distribution date of the last batch

Introduction to the Homeopathic Pharmacopoeia Convention of the United States (HPCUS)

A nongovernmental, nonprofit, scientific organization of experts who have appropriate training and experience, and have demonstrated add'l knowledge and interest in the principles of homeopathy. Works closely with the FDA. Update the HPUS. Divides into two sections: General Pharmacy & Drug Monographs. Contains approximately 1,300 monographs.

Definition of Homepathic Drugs

Any drug labeled as being homeopathic that is listed in HPUS, an addendum to it or its supplements. Potencies are specified in terms of dilution. They must meet the standards for strength, quality and purity set forth in HPUS. (Homeopathic Pharmacopoeia of the US) HPUS is declared a legal source of information on homeopathic drug products- a compilation of standards for source, composition and preparation of homeopathic drugs.

More Chapter 27 Questions

Question 1: What is an MOU a. Memorandum of utilization b. Memo of understanding c. Memorandum of understanding d. Memo of utilization Question 2: What types of claims are valid under federal Law a. NLEA claims for dietary content b. NLEA allowable health claims c. FDAMA allowable claims d. Qualified claims e. All of the above Question 3: How does a dietary supplement fact box differ from a nutritional fact box? a. The order of which the ingredients are displayed may vary, and zero value lines may not be displayed on dietary fact boxes b. There is no difference between dietary supplement fact boxes and nutritional fact boxes c. The order of which ingredients are displayed may vary on nutritional fact boxes d. Zero value lines must always be displayed on dietary supplement boxes Question 4: True / False the definition of labels/labeling for dietary supplements is consistent with all other definitions for labels / labeling Question 5:True / False dietary supplement regulation is mainly governed by the Nutritional Labeling Education Act of 1990.

Claims Permitted: Statement of Nutritional Support

o May discuss the benefit of the nutrient in relation to a classic nutrient deficiency disease o The role of a nutrient in affecting the structure or function of the human body or it's systems o Documented mechanisms by which a nutrient or dietary ingredient acts to maintain the structure or function of the body or general well being supported from the consumption of the ingredient. o All such claims must be truthful / not misleading o Claims made about classic nutrient deficiency disease must disclose the frequency of occurrence of the disease · In order to legally make any type of claim about dietary supplement products, the manufacturer must have data to substantiate the claim.

"Qualified Health Claims"

o These claims are based on the first amendment. FDA is not allowed to reject health claims unless a reasonable disclaimer could not also be given. The disclaimers are what qualify the health claim. o Typically not based on data that meet the standard of significant scientific agreement required for health claims o Another long list

Good Manufacturing Practices

· All firms that manufacture, prepare, propagate, compound or otherwise process homeopathic drugs must register as drug establishments in conformance with Section 510 of the FD&C Act and 21 CFR 207

Third party literature

· Allowed for under section 403B of DSHEA · A publication, including an article, a chapter in a book or an official abstract of a peer reviewed scientific publication that appears in an article and was prepared by the author or editors of the publication which is reprinted in its entirety shall not be defined as labeling when used in connection with the sale of a dietary supplement to consumers · Requirements o Must be truthful and no misleading o Not promote a particular manufacturer or brand of a dietary supplement o Be displayed or presented with other such items on the same subject matter in order to give a balanced view o Be displayed physically separated from the dietary supplements o Not have appended to it any information by sticker or other method · Shall not apply to or restrict a retailer or wholesaler of dietary supplements in any way whatsoever in the sale of books or other publications

History

· Between 1941 and 1979 tried to establish many rules to regulate the dosages of dietary supplements that could be sold without a prescription. After litigation no final rules were enacted and proposed rules were withdrawn · In 1989 FDA issues a warning against the use of L-Tryptophan products and subsequently recalled them after evidence was found that linked them to a rare blood disorder eosinophilia

Import and Export Regulations

· Bioterrorism Act of 2002, Section 307, added Section 801(m) to the FD&C Act requiring that FDA receive prior notice for food imported or offered for import into the US. If an article of food arrives at the port of arrival with inadequate prior notice, the food is subject to refusal of admission. · Prior notice submitted to FDA electronically via either the US Customs and Border Protection (Customs) Automated Broker Interface (ABI) or the Automated Commercial System (ACS) or FDA's Prior Notice System Interface (PNSI). · Prior notice must be receive and confirmed no more than 5 days before arrival and no less than: 2 hours by land, 4 hours by air or rail, and/or 8 hours by water. · Failure to submit prior notice can result in US bringing civil, criminal and debarment actions/ · Regulatory action for violations can include: refusal, hold, injunction, prosecution, debarment, customs seizure and assessment of civil monetary penalties. · The Bioterrorism Act requires domestic and foreign facilities that manufacture, process, pack or hold food for consumption in the US to register with FDA. Dietary supplements and dietary ingredients are regulated as foods by FDA. · Domestic facilities are required to register whether or not food from the facility enters interstate commerce. Foreign facilities are also required to register unless food from that facility undergoes further processing by another foreign facility before the food is exported to the US. · Foreign facilities are required to designate a US agent for registering. · Registrants must register using Form FDA 3537 · FDA issues the "certificate of free sale" as an export certificate for food, including dietary supplements. A food intended for export must not be deemed to be adulterated or misbranded under the act if it accords to the specs of the foreign purchaser, not in conflict with the laws of the exporting country, labeled that it is intended for export, not sold domestically.

Other regulation

· Bioterrorism Act requires facilities that manufacture, process, hold or package food to register with the FDA. · FDA has stated that according to the act, dietary supplements are a food and therefore must be registered.

Adverse Event Reporting

· December 2006, President Bush signed into law the Dietary Supplement and Nonprescription Drug Consumer Protection Act. This law amends the FD&C Act with respect to adverse event reporting and record keeping for dietary supplements. The mfgr, packer or distributor whose name appears on the label is required to submit to FDA all serious adverse event reports associated with the use of the dietary supplement. Effective date for compliance was December 2007. · Adverse Event is any health related event associated with the use of a dietary supplement that is adverse. · Serious Adverse Event: an adverse event that results in death, life-threatening experience, inpatient hospitalization, persistent or significant disability, in capacity, congenital anomaly or birth defect. Medical or surgical intervention. · "Responsible person" required to submit MedWatch Form 3500A along with a copy of the label no later than 15 business days. FDA requires mandatory reports be submitted in hard copy by mail only. · Data elements: identifiable injured person, identifiable initial reporter, responsible person's identity and contact information, suspect dietary supplement, serious adverse event or fatal outcome. · Responsible person must retain records related to each report for 6 years. o Should also include copies of the serious adverse event report to FDA on MedWatch Form 3500A, any new medical information, any report to FDA of new medical information, communications between the responsible person, initial reporter, any other person(s) who provided information related to the adverse event. · Any new medical information received within one year of the initial report must be submitted to FDA within 15 business days or receipt. · Dietary supps labeled after 22 December 2007 need to include a domestic address or phone number at which the responsible person can receive adverse event reports.

Definition of Dietary Ingredients and Dietary Supplements

· Definition per DSHEA · "products (other than tobacco) intended to supplement the diet that bear or contain one or more of the following dietary ingredients: o A vitamin o A mineral o An herb or other botanical o An amino acid o A dietary substance for use by man to supplement the diet by increasing the total dietary intake; or o A concentrate, metabolite, constituent, extract or a combination of any ingredient mentioned above o Further dietary supplements are products intended for ingestion, are not represented for use as a conventional food or as a sole item of a meal or the diet and are labeled as dietary supplement · Liquid products that suggest through their service size, packaging or recommended daily intake that they are intended to be consumed in amounts that provide all or a significant part of the entire daily drinking fluid intake of an average person in the US are represented as beverages · Additionally the name of a product can represent the product as conventional food, names that include things such as "beverage", "drink", "water", "juice" or similar terms represent the product as conventional food.

NDI (New Dietary Ingredients) Notifications

· Dietary supplements, ingredients and products are not subject to premarket approval · However FDA must be notified prior to introducing any dietary ingredients that were not marketed in the US prior to October 15 1994 · Notification must be given to the Office of Nutritional Products, Labeling and Dietary Supplements (ONPLDS) at least 75 days before introducing the NDI into interstate commerce · Must include: o Name and address of the manufacturer or distributor o NDI name including the Latin binomial name of any herb or other botanical o Description of the products that contain the NDI along with the level of the NDI in the product o Conditions of ordinary use of the supplement o History of use or other evidence establishing the safety of the NDI under conditions of use including any citation to and reprint, copy or English translation of published articles or other evidence establishing that the NDI will be reasonably expected to be safe o Signature of the person designated by the manufacturer or distributor of the NDI · FDA will acknowledge and provide the date of receipt of the NDI Notification · The NDA may not be introduced into commerce for 75 days following the filing date · FDA will put the NDA notification, with the exception of any trade secret or confidential information, "on public display" 90 days after submission · Failure of the FDA to respond to a notification does not constitute a finding by the agency that the NDI or dietary supplement is safe or not adulterated.

Supplement Advertising and the FTC

· FTCs Division of Advertising Practices is the enforcer of federal truth in advertising laws · FDA works closely with the FTC under a 1971 MOU · FDA has primary responsibility for claims appearing on product labeling · FTC has primary responsibility for claims made in advertising

Labels and Labeling

· Labels are any display of written, printed, or graphic matter on the immediate container of any article or any such matter affixed to any consumer commodity or affixed to or appearing on the package containing any user commodity · Labeling includes all written, printed or graphic matter accompanying an article at any time while such article is in interstate commerce or held for safe after shipment or delivery in interstate commerce · Labeling regulations on Dietary Supplements can be found in 21 CFR 101.9 · Must include o Statement of identity o Net quantity of contents statement o An ingredient list o The address of the manufacturer o Must declare the presence of major allergens o Facts box that declares the nutrients present in the product · Dietary supplement facts boxes are very similar to food facts boxes o however while both must list threshold levels of certain ingredients, the order of the ingredients varies between food and dietary supplement labeling o another key difference is that in nutrition boxes, zero value fields must be shown such as fats. In dietary supplement labels, these can be omitted

Claim submission

· Manufacturers must notify ONPLDS of any claims or statements of nutritional support they wish to make about their product · Must occur within 30 days of first using the claim · FDA may object to the usage of the claim

Claims permitted

· NLEA permitted nutrient content claims such as "high in fiber" or "rich source of vitamin C" · Then there was a list citing the various regulations associated with various claims. · NLEA also provided for the establishment of allowable health claims, petitions for such claims may be granted when there is documented evidence in publically available documents. · Another list of regulations associated with various claims · "Health Claims" are claims based on current, published authoritative literatures o Claims can be made 120 days after the submission of the claim o FDAMA claim notifications must include § the exact wording of intended claim § concise description of the basis for the claim § copies of the references authoritative statements § and for a health claim a balanced representation of the scientific literature relating to the relationship between a nutrient and a disease or health related condition § for a nutrient related claim a balanced representation of the scientific literature relating to the nutrient level to which the claims refer to. o Current authorized FDAMA claims § Choline Nutrient Content Claims § Fluoride and the Risk of Dental Caries § Potassium and the risk of High Blood Pressure and Stroke § Saturated Fat, Cholesterol and Trans Fat and the Risk of Heart Disease § Substitution of saturated fat with unsaturated fatty acids and risk of heart disease § Whole grain foods and the risk of heart disease and certain cancers

Labeling and Advertising

· Subject to the applicable FDA regulations for labeling, advertising and promotion. Must comply with the provisions of Sections 502 and 503 of the FD& C Act and 21 CFR 201. · Label shall contain "Homeopathic" in a prominent way. · Statement of ingredients. · The letters "HPUS" should be appended to the name of each official drug. · A statement that states the letters HPUS indicate that the component(s) in this product are officially monographed in the Homeopathic Pharmacopoeia of the United States. The designation is restricted. · Manufacturer, packer or distributor's name and place of business.