Short Overview of FDA Regulations and Guidance for the Traditional Chinese Medicine (TCM)

Traditional Chinese Medicine (TCM) is an essential part of the healthcare system in China and several Asian countries, which is considered a Complementary or Alternative Medical (CAM) System in most Western countries (1). Today about 80% of the world still uses plants and plant-based products to  treat  medical conditions (2).

During the past 30-40 years, the healthcare and scientific communities have paid increasing attention to the role of Traditional Chinese Medicine in preventing and treating chronic diseases and metabolic syndromes. Increasing use of TCM approaches in the United States contributed to the establishment in 1998 of the National Center for Complementary and Alternative Medicine within the U.S. National Institutes of Health (NIH). This led to a dramatic expansion in the number and quality of clinical trials funded to study TCM and botanical products. Today, many leading health care centers in the U.S. like the Mayo Clinic, Cleveland Clinic, and Johns Hopkins offering TCM practices to treat chronic diseases.

What Is Traditional Chinese Medicine?

Traditional Chinese Medicine, by definition,  according to the U.S. National Cancer Institute (NCI) at NIH is:

"A medical system that has been used for thousands of years to prevent, diagnose, and treat disease. It is based on the belief that qi (the body's vital energy) flows along meridians (channels) in the body and keeps a person’s spiritual, emotional, mental, and physical health in balance.

Traditional Chinese medicine aims to restore the body’s balance and harmony between the natural opposing forces of yin and yang, which can block qi and cause disease. Traditional Chinese medicine includes acupuncture, diet, herbal therapy, meditation, physical exercise, and massage. Also called Oriental medicine and TCM"(3).

Short Overview of FDA Regulations and Guidance for the Traditional Chinese Medicine (TCM) By Lin Zhang

What Are Botanical Drugs?

Botanical products are finished, labeled products that contain plant-derived ingredients. FDA describes the "botanicals" to mean products derived from "plant materials, algae, macroscopic fungi, and combinations thereof"(4). Internationally, botanical products are regulated under different classifications, some of which are:

• Dietary supplements in the U.S.

• Herbal medicines (i.e., Europe)

• Traditional herbal medicines (i.e., China)

Botanical drugs may be available in various forms, including solutions, powders, tablets, capsules, topicals, or injectables.

(However, FDA also describes fermentation products and highly purified or chemically modified botanical substances are NOT considered botanical drug products)(4). Due to these unique characteristics, FDA generally considers the entire botanical drug substance to be the active ingredient (API) of the botanical drug product.

New Botanical Drug Guidance (2016)

In 2016, FDA published a revised guidance document for industry on botanical drug development (4). This guidance describes the FDA Center for Drug Evaluation and Research’s (CDER’s) current thinking on appropriate development plans for botanical drugs to be submitted in new drug applications (NDAs) and specific recommendations on submitting investigational new drug applications (INDs) in support of future NDA submissions for botanical drugs.

The recommendations of revised FDA Botanical Guidance for early-phase trials remains the same. This Guidance provides additional specific recommendations to better address late-phase development and NDA submission for botanical drugs. It proposes an integrated (the so-called totality of evidence) approach to ensure the consistency of quality and thus therapeutic effects of botanical drug products for approval and marketing. This guidance also provides general information on the over-the-counter (OTC) drug monograph system for botanical drugs. A botanical drug product may be marketed in the United States under either an over-the-counter (OTC) drug monograph or an approved new drug application (NDA).

The most critical element of the IND application for botanical products is the Chemistry, Manufacturing and Controls (CMC) information that herbal extracts manufacturers must ensure the botanical drug’s identity, purity, quality, strength, potency and consistency as well as assessment of the safety and toxicity of botanical drugs in clinical trials because botanical products certain unique characteristics and a complex mixture of components, which are often not be fully identified and understood (5).

Please note that this guidance does not establish legally enforceable responsibilities for any person and is not binding on the FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations (4). However, the level of clinical efficacy and safety requirements is the same for botanical and non-botanical drugs.

Current Botanical Drug Development

Botanicals have historically been a source of new drugs and is expanding continuously (2). A survey of botanical drug applications across the therapeutic divisions within CDER, FDA showed currently, there are 680 pre-INDs and INDs botanical investigational new drug applications going through FDA's clinical trials. Among these drugs, approximately 1/3 are commercial, 2/3 are research-based, 2/3 are single botanical raw material and 1/3 are multiple botanical raw materials, majority are in phase II, and/or Phase III trials (6).

The share of botanical investigational new drugs as of 2017, by therapeutic area as follows:  more than one-third of all such botanical INDs were for oncologic therapy (34%), dermatological Dental (10%), anesthesia, analgesia and addiction (10%) (7).

Within the past decade FDA has approved two NDAs for prescription botanical new drugs, the first NDA was Veregen®, a treatment for genital and perianal warts that is derived from green tea (Camellia sinensis Kuntze) (8). The second NDA was Fulyzaq™, an indicator drug for HIV-associated diarrhea extracted from the blood-red latex of the South American croton tree (9).

General Principles of the IND Submission

FDA’s primary objectives in reviewing an IND are, in all phases of the clinical investigation, to assure the safety and rights of subjects; the FDA’s review of Phase I submissions will focus on assessing the safety of the respective investigation(s); whereas the FDA’s review of Phase II and III submissions will also include an assessment of the scientific quality of the respective investigations and the likelihood that the investigations will yield data capable of meeting statutory standards for granting marketing approval.

IND Application: Content and Format

An IND application for initial submission to the FDA shall include, in the following order: (10)

1. A completed FORM FDA 1571 and 1572.

2. Table of Contents

3. Introductory Statement and General Investigational Plan

4. Investigator’s Brochure

5. Clinical Protocol(s)

6. Chemistry, Manufacturing, and Control (CMC) Information

7. Drug Labeling

8. Pharmacology and Toxicology Information

9. Previous Human Experience with the Investigational Drug

10. Additional Information

11. FDA-Requested Relevant Information

Perspective of FDA Botanical Review Team

IND applications for botanical drugs are very similar in format and content to INDs for conventional drugs. However, some specific issues need to be addressed carefully and the following considerations should be taken:

• FDA encourages research and development of botanicals as new drugs

• Pharmacology and toxicology of botanical drugs

• Ensure quality assurance and data management in clinical trial

• Ensure authenticity and quality control of Botanical Raw Materials (BRM) following Good Agricultural and Collection Practices and Good Manufacturing Practices (GACP-GMP) for Botanical Materials

• Comprehensive systematic approach to monitor the chemical profiles of botanical materials, intermediates, substances, and products (CMC information)

• Extensive review, clinical and research evidence of previous experiences and current uses that may provide some indication of the safety profile of botanical products, i.e. traditional Chinese medicines

• Market trend and history as well as adverse reaction events reports

• Follow the 2016 revised FDA Guidance for Industry: Botanical Drug Development

• Take an advantage of Pre-IND Consultation Program and Pre-IND Meeting with FDA officials by contacting Office of Drug Evaluation I~IV (11)

• Most importantly, keep in mind two KEY words: safety and efficacy for INDs in each phase of the drug development process.

Importance of FDA Pre-IND Meeting

It is strongly recommended that sponsors compile all available information and discuss it, along with the design of the proposed preclinical and clinical trials, with the appropriate division of FDA in a pre-IND meeting. By discussing the development program with FDA prior to implementation, the sponsor receives critical feedback on the proposed studies and the acceptability of information. For such meetings, the sponsor should always request that representatives of the Botanical Review Team attend the meeting. All aspects of the product development plan should be discussed during the meeting (11).
                       
eCTD format and submission to FDA

It is noteworthy that as of May 5, 2017, Electronic Common Technical Document (eCTD) has become the standard format for submitting applications, amendments, supplements, and reports to FDA for INDs, NDAs, ANDAs, BLAs, and master files. The FDA’s goal is to reduce the time required to process submissions and route files from to the reviewer as quickly as possible. In addition, exchange of regulatory information between regulatory authorities will be simplified (12).

FDA Administrative Actions

1. In general, an IND goes into effect (a) thirty (30) days after the FDA receives the IND,
2. FDA will notify the sponsor in writing of the date it receives the IND
3. An investigator may not administer an investigational new drug to human subjects until the IND goes into effect.

According to the FDA, botanical products intended to be marketed as drugs in the United States are expected to meet the same standards as non-botanical drugs for quality, safety, and efficacy by law.

References

1. Chan E1, Tan M, Xin J, Sudarsanam S, Johnson DE. Curr Opin Drug Discov Devel. Interactions between traditional Chinese medicines and Western therapeutics.  2010 Jan;13(1):50-65.

2. Ekor M, Front Pharmacol, The growing use of herbal medicines: issues relating to adverse reactions and challenges in monitoring safety. 2014, 4: 177.

3. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/traditional-chinese-medicine

4. Food & Drug Admin., Guidance for Industry: Botanical Drug Development  (2016)

5. Kyungseop Ahn, BMB Rep. The worldwide trend of using botanical drugs and strategies for developing global drugs 2017 Mar; 50(3): 111–116.

6. https://clinicaltrials.gov

7. Matej Mikulic,   Statista, Share of botanical investigational new drugs as of 2017, by therapeutic area, Nov 7, 2018,

8. Chen ST, Dou J, Temple R, Agarwal R, Wu KM, Walker S.  Nat Biotechnol. New therapies from old medicines. 2008 Oct;26(10):1077-83. 

9. Yeo QM, Crutchley R, Cottreau J, Tucker A, Garey KW.     Drugs Today (Barc). Crofelemer, a novel antisecretory agent approved for the treatment of HIV-associated diarrhea. 2013 Apr;49(4):239-52.

10.  (US-Code of Federal Regulations (CFR) -Title 21, Sec. 312.82)

11. PRE-IND Consultation Contacts at https://www.fda.gov/media/77025/

12. FDA: Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications Guidance for Industry.

About the Author:

Lin Zhang, M.D., senior director of a health care industry company in the United States. With the experience in clinical medicine, biotechnology, health industry and other fields, he is responsible for the research and development of plant medicine, functional food and health products. He was a clinician and worked for the National Cancer Institute, FDA and the National Cancer Center of Japan for many years.

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