Regulatory and Industry Requirements for Botanical Drug Products Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D Department of Pharmaceutics KLE University College of Pharmacy BELGAUM – , Karnataka, India Cell No: /01/20111BIRDEM & ANRAP, Dhaka, Bangladesh

Herbal Medicines Although modern medicine is well developed in most of the world, large sections of the population in developing countries still rely on the traditional practitioners, medicinal plants and herbal medicines for their primary care. Moreover during the past decades, public interest in natural therapies has increased greatly in industrialized countries, with expanding use of medicinal plants and herbal medicines. 01/01/20112BIRDEM & ANRAP, Dhaka, Bangladesh

Traditional Herbal Medicines and Human Health Herbal medicines which formed the basis of health care throughout the world since the earliest days of mankind are still widely used, and have considerable importance in international trade. Recognition of their clinical, pharmaceutical and economic value is still growing, although this varies widely between countries. 01/01/20113BIRDEM & ANRAP, Dhaka, Bangladesh

There are different ways in which countries define medicinal plants or herbs or products derived from them, and countries have adopted various approaches to licensing, dispensing, manufacturing and trading to ensure their safety, quality and efficacy Traditional Herbal Medicines and Human Health 01/01/20114BIRDEM & ANRAP, Dhaka, Bangladesh

Despite the use of herbal medicines over many centuries, only a relatively small number of plant species has been studied for possible medical applications. Safety and efficacy data are available for an even smaller number of plants, their extracts and active ingredients and preparations containing them. Traditional Herbal Medicines and Human Health 01/01/20115BIRDEM & ANRAP, Dhaka, Bangladesh

Regulation and Registration of Herbal Medicines The legal situation regarding herbal preparations varies from country to country. Developing countries, however, often have a great number of traditionally used herbal medicines and much folk-knowledge about them. 01/01/20116BIRDEM & ANRAP, Dhaka, Bangladesh

GENERAL REGULATORY APPROACHES Many botanical products are used widely in the United States. Depending on its labeling and intended use, a botanical product can be a food, a dietary supplement, and/or a drug. 01/01/20117BIRDEM & ANRAP, Dhaka, Bangladesh

Botanicals used for food and consumed primarily for their taste, aroma, or nutritive value are regulated as foods. Botanicals can also be dietary supplements if they are labeled as dietary supplements and otherwise meet the dietary supplement definition. GENERAL REGULATORY APPROACHES 01/01/20118BIRDEM & ANRAP, Dhaka, Bangladesh

GENERAL REGULATORY APPROACHES If a botanical product is intended to affect the structure or function of the body but does not meet the definition of a dietary supplement, or does not meet the requirements for making a structure/function. 01/01/20119BIRDEM & ANRAP, Dhaka, Bangladesh

GENERAL REGULATORY APPROACHES As noted above, a botanical product is subject to regulation as a drug under section 201(g)(1)(B) of the Act if it is intended for use in diagnosing, mitigating, treating, curing, or preventing disease. 01/01/201110BIRDEM & ANRAP, Dhaka, Bangladesh

GENERAL REGULATORY APPROACHES Under section 505(b) of the Act, a drug must be marketed under an approved NDA unless the product is excluded from the definition of a new drug. Certain products that FDA determines are generally recognized as safe and effective in accordance. 01/01/201111BIRDEM & ANRAP, Dhaka, Bangladesh

Marketing Under OTC Drug Monograph Versus Approved NDA A botanical drug product may be marketed in the United States under (1) an OTC drug monograph or (2) an approved NDA or ANDA. A botanical product that has been marketed in the United States for a material time and to a material extent for a specific OTC drug indication may be eligible for inclusion in an OTC drug monograph. 01/01/201112BIRDEM & ANRAP, Dhaka, Bangladesh

When a final OTC drug monograph is published for a specific use of a botanical drug, any person may market a product containing the same substance and for the same use, provided the labeling and other active ingredients (if present) are in accord with all relevant monographs and other applicable regulations. Marketing Under OTC Drug Monograph Versus Approved NDA 01/01/201113BIRDEM & ANRAP, Dhaka, Bangladesh

In contrast, when a product is approved under an NDA, the approval is specific to the drug product that is the subject of the application. Mrketing exclusivity for either 5 years (if it is a new chemical entity) or 3 years from the time of approval, even in the absence of patent protection. Marketing Under OTC Drug Monograph Versus Approved NDA 01/01/201114BIRDEM & ANRAP, Dhaka, Bangladesh

CMC Information for Botanical Drug Products Because of the complex nature of a typical botanical drug and the lack of knowledge of its active constituent's. FDA may rely on a combination of tests and controls to ensure the - identity, purity, quality, strength, potency, and consistency of botanical drugs. 01/01/201115BIRDEM & ANRAP, Dhaka, Bangladesh

CMC Information for Botanical Drug Products These tests and controls include 1) Multiple tests for drug substance and drug product (e.g., spectroscopic and/or chromatographic fingerprints, chemical assay of characteristic markers, and biological assay), 2) Raw material and process controls (e.g., strict quality controls for the botanical raw materials and adequate in-process controls), and 3) Process validation (especially for the drug substance). 01/01/201116BIRDEM & ANRAP, Dhaka, Bangladesh

CMC and Toxicology Information to Support Initial Studies Many botanical products are legally available in the United States as dietary supplements. Given the wide availability of such products outside of clinical trials, it is important to assess the effectiveness of such products. 01/01/201117BIRDEM & ANRAP, Dhaka, Bangladesh

To support initial clinical trials, the nonclinical pharmacology and toxicology information that must be provided for legally available botanical products with no known safety issues. In most cases, additional toxicology and CMC data will not be required for such initial trials. CMC and Toxicology Information to Support Initial Studies 01/01/201118BIRDEM & ANRAP, Dhaka, Bangladesh

Applicability of Combination Drug Regulations Botanical drug products that are derived from a single part of a plant (e.g., leaves, stems, roots, or seeds), or from a single species of alga or macroscopic fungus (e.g., a mushroom), are not considered to be fixed- combination drugs. 01/01/201119BIRDEM & ANRAP, Dhaka, Bangladesh

Consequently, they do not have to meet the requirements for combination drugs, principally the need to demonstrate that each component or active ingredient makes a contribution to claimed effects. Applicability of Combination Drug Regulations 01/01/201120BIRDEM & ANRAP, Dhaka, Bangladesh

MARKETING A BOTANICAL DRUG UNDER AN OTC DRUG MONOGRAPH A botanical product that has been marketed in the United States for a material time and to a material extent for a specific OTC indication may be eligible for consideration in the OTC drug monograph system. Currently, there are several botanical drugs, including cascara, psyllium, and senna, that are included in the OTC drug review. 01/01/201121BIRDEM & ANRAP, Dhaka, Bangladesh

For a botanical drug substance to be included in an OTC drug monograph, there must be published data establishing general recognition of safety and effectiveness, usually including results of adequate and well-controlled clinical studies. Requirements related to safety, effectiveness, and labeling for drugs to be included in an OTC drug monograph. MARKETING A BOTANICAL DRUG UNDER AN OTC DRUG MONOGRAPH 01/01/201122BIRDEM & ANRAP, Dhaka, Bangladesh

MARKETING A BOTANICAL DRUG UNDER AN NDA A botanical drug product that is not generally recognized as safe and effective for its therapeutic claims is considered a new drug. 01/01/201123BIRDEM & ANRAP, Dhaka, Bangladesh

NDA must contain substantial evidence of effectiveness derived from adequate and well- controlled clinical studies, evidence of safety, and adequate CMC information. The format of an NDA submission and the requirements for its various sections are discussed in several CDER guidance documents. MARKETING A BOTANICAL DRUG UNDER AN NDA 01/01/201124BIRDEM & ANRAP, Dhaka, Bangladesh

INDs FOR BOTANICAL DRUGS A.IND Information for Different Categories of Botanicals B.Basic Format for INDs 1.Cover Sheet 2.Table of Contents 3.Introductory Statement and General Investigational Plan 4.Investigator’s Brochure 5.Protocols 6.Chemistry, Manufacturing and Controls (CMC) 7.Pharmacology and Toxicology Information 8.Previous Human Experience With the Product 01/01/201125BIRDEM & ANRAP, Dhaka, Bangladesh

INDs FOR PHASE 1 AND PHASE 2 CLINICAL STUDIES OF LAWFULLY MARKETED BOTANICAL PRODUCTS WITHOUT SAFETY CONCERNS A.Description of Product and Documentation of Human Use 1.Description of Botanical Used 2.History of Use 3.Current Marketed Use B. Chemistry, Manufacturing and Controls 1.Botanical Raw Material 2.Botanical Drug Substance 3.Botanical Drug Product 4.Animal Safety 5.Placebo 6.Labeling 7.Environmental Assessment or Claim of Categorical Exclusion 01/01/201126BIRDEM & ANRAP, Dhaka, Bangladesh

C. Pharmacology/Toxicology Information 1.All Marketed Botanical Products 2.Foreign-Marketed Botanical Products D. Bioavailability E. Clinical Considerations INDs FOR PHASE 1 AND PHASE 2 CLINICAL STUDIES OF LAWFULLY MARKETED BOTANICAL PRODUCTS WITHOUT SAFETY CONCERNS 01/01/201127BIRDEM & ANRAP, Dhaka, Bangladesh

INDs FOR PHASE 1 AND PHASE 2 CLINICAL STUDIES FOR NONMARKETED BOTANICAL PRODUCTS AND PRODUCTS WITH KNOWN SAFETY CONCERNS A.Description of Product and Documentation of Human Use 1.Description of Botanical Used 2.History of Use 3.Current Investigational Use B. Chemistry, Manufacturing and Control 1.Botanical Raw Material 2.Botanical Drug Substance 3.Botanical Drug Product 4.Placebo 5.Labeling 6.Environmental Assessment or Claim of Categorical Exclusion 01/01/201128BIRDEM & ANRAP, Dhaka, Bangladesh

C. Nonclinical safety Assessment 1.Traditional Preparations 2.Others 3.Products with Known Safety Issues D. Bioavailability E. Clinical Considerations INDS FOR PHASE 1 AND PHASE 2 CLINICAL STUDIES FOR NONMARKETED BOTANICAL PRODUCTS AND PRODUCTS WITH KNOWN SAFETY CONCERNS 01/01/201129BIRDEM & ANRAP, Dhaka, Bangladesh

INDs FOR PHASE 3 CLINICAL STUDIES OF ALL BOTANICAL PRODUCTS A.Description of Product and Documentation of Human Experience B.Chemistry, Manufacturing and Control 1.Expanded Clinical Studies a.Botanical raw material b.Botanical drug substance c.Botanical drug product 2. End-of-Phase 3 Clinical Studies and Pre-NDA Considerations 01/01/201130BIRDEM & ANRAP, Dhaka, Bangladesh

C. Nonclinical Safety Assessment 1.Repeat-Dose General Toxicity Studies 2.Nonclinical Pharmacokinetic/Toxicokinetic Studies 3.Reproductive Toxicology 4.Genotoxicity Studies 5.Carcinogenicity Studies 6.Special Pharmacology/Toxicology Studies 7.Regulatory Considerations D. Bioavailability and Clinical Pharmacology E. Clinical Considerations INDs FOR PHASE 3 CLINICAL STUDIES OF ALL BOTANICAL PRODUCTS 01/01/201131BIRDEM & ANRAP, Dhaka, Bangladesh

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OTC Drug Monograph Review Process 01/01/201136BIRDEM & ANRAP, Dhaka, Bangladesh

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