FDA Regulatory Requirements for Botanical INDs. By Jiayao Eric Wang, MD, CCRP, RAC

Transcription

1 FDA Regulatory Requirements for Botanical INDs By Jiayao Eric Wang, MD, CCRP, RAC 36 August 2009

2 The notion of plants as sources of healing is as old as medicine itself. Many valuable drugs used today were adopted through the study of traditional medicines and natural products, which may be used directly or after chemical modification. Medical research shows that using individual ingredients alone may not be as effective as combining them in a formula. It also shows that herbal formulas containing multiple active ingredients can offer solutions to complex problems within a single pill, with synergy of the ingredients occurring inside the body. To be marketed as a drug, a botanical product must go through a scientific validation process to prove its safety, efficacy and consistency. Safety and efficacy evaluations are similar to those required for chemical drugs. However, ensuring the quality of botanical drugs remains controversial, because of their complexity and the constraints of methodology. The challenge of quality assurance has been a major obstacle to US Food and Drug Administration (FDA) regulation of botanicals as drugs. On the other hand, the popular use and substantial demand for botanical products in the US have drawn attention from both the agency and the industry. In 2004, FDA finally promulgated Guidance for Industry: Botanical Drug Products (usually called Botanical Guidance). This guidance outlines FDA s current thinking on regulatory issues and Investigational New Drug (IND) requirements for botanical products and explains how to determine whether a botanical product should be marketed by its intended use, as a food, dietary supplement, drug, medical device or cosmetic. Table 1. Comparison of Botanical Drugs and Chemical Drugs Chemistry Active Constituent(s) Quality Control Attributes GMP Required Nonclinical Requirements for IND Clinical Evaluation Chemical Drugs Synthesized or purified from natural sources Clearly identified Well-defined qualitative and quantitative controls For the manufacture of drug substance Standard testing Standard Phase 1 to 3 Botanical Drugs Complex mixture; chemical constituents are not well defined. Unknown in most cases Characteristic controls, and may not be clinically, directly relevant. Extended to raw materials: supplier change should be pre-approved. Reduced or delayed; Previous uncontrolled human experiences could be used as part of the safety evaluation to expedite initial clinical studies. Initiate more-definitive trials early, instead of pilot or typical Phase 1. Regulatory Focus 37

3 Table 2. Comprehensive Summary of FDA s Requirements for Botanical INDs Description of Botanicals Used History of Use IND Requirements Phase 1 or 2 Phase 3 For Lawfully Marketed Botanical Products (US or Foreign) Without For Non-Marketed Botanical Products and Products With Known Safety Concerns Safety Concerns A. Description of Product and Documentation of Human Experience Common name; synonyms; botanical name; pharmaceutical name; characteristic marker, if known Morphological and anatomical description; photograph; natural habitat and geographical distribution; current sources of raw materials; endangered species statement Information for drug product and each ingredient Method of preparation; dose and route; medical claims; safety; geographical uses and experience Current investigational use use of drug product and each ingredient B. Chemistry, Manufacturing and Controls Certificate of Authenticity Organoleptic, macroscopic and microscopic exams Growers and suppliers; harvest location; growing conditions; harvest time and stage of growth; preparation; storage Fingerprint; chemical identity Name and address of processor Preparation procedures and process controls Quality control tests and analytical procedures, including botanical identification, chemical identification, fingerprint, bioassay, heavy metals, microbial limits, pesticides, toxins, foreign materials and adulterants Photocopy of voucher specimen Certificate of Analysis Storage conditions and container/closure system General method of preparation; indicate whether followed traditional process Qualitative and quantitative descriptions Name and address of manufacturer Raw material acceptance specifications and receiving tests Quality control tests: appearance, fingerprints, chemical assay, biological assay, strength, heavy metals, microbial limits Residue on ignition, water content, residual solvents, pesticides, radioisotope contaminants, adventitious toxins, endogenous toxins Validation reports of all analytical procedures Reference standards Batch analysis Container/closure Stability Animal safety test for injectables Labeled with qualitative and quantitative descriptions Single clinical batch recommended Multiple clinical batches recommended Qualitative and quantitative descriptions Certificate of Analysis Test methods Name and address of manufacturer Drug substance acceptance specifications and receiving tests Description of manufacturing process Quality control tests: appearance, fingerprint, chemical assay, biological assay, strength, microbial limits and other dosage specific attributes Residual solvents; adventitious toxins Validation reports of all analytical procedures Batch analysis Current Marketed Use Nature and extent of the current worldwide Botanical Raw Material Botanical Drug Substance Botanical Drug Product Container/closure Stability Placebo Description of components, if applicable 38 August 2009

4 Labeling Copy of the label for marketed product Proposed clinical label with general descriptions Quantitative description Environmental Claim of categorical exclusion Assessment Case-by-case determination if involves harvesting a wild species; required if extraordinary circumstances exist C. Nonclinical Safety Assessment US-marketed Products Previous human experience and available animal toxicity data for drug product and each ingredient Database search result for drug product, individual ingredients and known chemical constituents Non-US-marketed Annual sales, exposed population and Products adverse effects Nonmarketed If prepared according to a traditional methodology, N/A Products sufficient information might be available to support studies without standard nonclinical testing If NOT prepared according to a traditional methodology, nonclinical testing will be determined on a case-by-case basis Products with Known Nonclinical testing will be determined on a Safety Issues case-by-case basis All Product Repeat-dose general toxicity in two mammalian species at maximum feasible dose Reproductive toxicology Genotoxicity Carcinogenicity on a case-by-case basis Special pharmacology/toxicology on a caseby-case basis D. Bioavailability and Clinical Pharmacology PK and PD When feasible Drug-drug Interaction If applicable E. Clinical Considerations Protocol Design Instead of pilot or typical Phase 1, initiate more-definitive trials early Summarized from FDA Guidance for Industry: Botanical Drug Products (June 2004) In addition, the agency acknowledged the unique nature of botanicals and found it appropriate to apply regulatory policies that differ from those for synthetic, semi-synthetic or otherwise highly purified drugs. In particular, this guidance states that applicants may submit reduced documentation for nonclinical safety and chemistry, manufacturing and controls (CMC) to support an IND for initial clinical studies of botanicals that have been legally marketed in the US and/or another country as dietary supplements without any known safety concerns. FDA defines botanical drug as a drug product containing vegetable materials, which may include plant materials, algae, macroscopic fungi or a combination thereof, in all dosage forms. Botanical drugs are usually prepared as complex mixtures. Highly purified drugs derived from botanical sources, whose active constituents can be more readily identified and quantified, are not considered botanical drugs as such, and are beyond the scope this article. This article focuses on the unique regulatory requirements, particularly nonclinical and CMC requirements, for botanical INDs. FDA claims to apply the same standard to commercial and academic INDs. Characteristics of Botanical Drugs and FDA s Standpoint Raw Materials Plants are recognized as a rich source for medicines because they produce molecules characterized by intrinsic biological activity that evolved as a defense against disease or predators. Botanical raw materials are the starting point for manufacturing botanical drug substances. Obviously, medicinal plants can experience crop-tocrop variations due to natural changes in growing conditions. Further, once the harvested herbs are processed, some of nature s most basic elements air, moisture and even light can damage their potency and value. For these reasons, raw material quality control is a critical part of overall quality assurance for botanical drugs. Consequently, FDA requires quality control for botanical drugs to be extended to raw materials. Although FDA has no specific quality standards for botanical Regulatory Focus 39

5 raw materials, other compendial standards (Chinese, European and WHO) for medicinal plants could be considered reliable in science, achievable in practice and, most likely, acceptable to the agency. Active Constituent(s) The most biologically active compounds in medicinal plants, some having profound pharmacological significance, are typically the less-plentiful, secondary metabolites. In multicellular organisms such as plants, the formation of secondary metabolites is expressed as a specific feature of certain organs or tissues during restricted periods of their development and specialization. Their structure is often complex, and as a result these compounds perform very specific physiological functions in plants as well as in human diseases. For a complex botanical formula, there could be more than one active constituent in the drug product, yet in most cases, it is not technically feasible to identify them. Fortunately, FDA does not require such identification for initial clinical studies (Phase 1 or 2), but requires active constituents be identified, when feasible, during Phase 3 studies; otherwise, a direct or indirect clinically relevant characteristic marker(s) should be developed for marketing approval. Quality Control In its infancy, botanical product research was greatly limited due to the lack of technology. Quality control tests relevant to safety and efficacy are desirable but usually unavailable for botanical drugs. Therefore, quality control for botanicals relies on a combination of tests and controls, including multiple tests for drug substance and drug product, e.g., spectroscopic and/or chromatographic fingerprints; raw material and process controls; and process validation, especially for the drug substance. FDA accepts fingerprinting identification and strength expressed as dry weight as alternatives in the initial stage of clinical studies. Appropriate acceptance criteria for batch release need not be established until Phase 3. Nonclinical Requirements Usually, less nonclinical information is required to support the initial clinical trials for currently marketed botanical products compared to chemical drug products. For a botanical product that is not currently marketed lawfully in the US, but is administered orally and prepared, processed and used according to methodologies for which there is prior human experience, sufficient information may be available to support initial clinical studies without standard nonclinical testing. However, for a botanical drug with a route of administration other than oral, or with known safety issues, additional nonclinical information may be necessary before initial clinical studies. After initial clinical studies, further pharmacology/toxicology studies generally are needed before later clinical development phases and marketing approval. Previous clinical studies, if any, must be included in an IND to assist FDA in its overall safety assessment. Clinical Considerations In general, clinical evaluation of botanical drugs for safety and efficacy does not differ significantly from evaluation of chemical drugs. A sponsor need not differentiate the clinical effects of each molecular entity in a botanical product, and initial, controlled studies could be used to evaluate the entire product. Botanical drugs composed of multiple parts of a single species of botanical raw material, or of parts from different species of botanical raw materials, currently are subject to combination drug requirements. However, FDA is considering revising its regulations to exempt such botanical drugs from the combination drug requirements under certain circumstances. For a product that has been marketed with a known dose thought to be appropriate and well tolerated, there should be little need for pilot or typical Phase 1 studies, and uncontrolled observations are unlikely to be useful. Therefore, sponsors are strongly encouraged to initiate more-definitive trials early in the development program to determine whether a botanical product has efficacy for one or more claimed indications. FDA recommends the use of a single clinical batch from a single source for Phase 1 or 2 studies. The use of multiple batches for Phase 3 studies may be helpful to determine clinical impact from batch variance. Individualized treatments with multiple formulations in one trial are acceptable for FDA, and multiple formulations can be included in one IND if they are being studied under a single clinical trial. Table 1 compares the 40 August 2009

6 chemistry and regulatory requirements for botanical drugs and chemical drugs. Regulatory Requirements for Botanical INDs The general IND requirements are set forth in 21 CFR 312. Described in the Botanical Guidance, FDA tailored its requirements for botanical INDs based upon the different categories of botanical drugs and stage of clinical trials. Botanicals legally marketed as dietary supplements under the Dietary Supplement Health and Education Act of 1994 (DSHEA) often require very little new CMC or toxicological data to initiate Phase 1 or 2 trials, as long as there are no known safety issues associated with the product and it is to be used at approximately the same doses as those currently or traditionally used or recommended. A botanical drug known to have safety issues and produce serious and/or possibly life-threatening effects may need additional nonclinical data as well as product characterization in quality control to establish safe dosages and determine ways to better monitor potential toxicities in humans. If a botanical product shows promise of effectiveness in early trials, the potential for wider use will create a need for greater assurance of product quality and consistency and for expanded (i.e., Phase 3) clinical studies of safety and effectiveness. Table 2 provides a comprehensive summary of FDA s requirements for botanical INDs. perspective, the sponsor should establish a product-specific development strategy in the early stages of clinical development. References 1. Guidance for Industry: Botanical Drug Products (June 2004). Accessible at AboutFDA/CentersOffices/CDER/ucm pdf. 2. Duo J. Selected Topics on the Regulatory Review of Botanical IND and NDA. Presented at the 44 th Drug Information Association Annual Meeting, Boston FDA first botanical drug approval: NDA Accessible at cder/drugsatfda. Author Jiayao Eric Wang, MD, CCRP, RAC, is general manager of SkinGenix Inc., a company specializing in botanical drug development. He has more than 20 years experience in medical practice, biomedical research and botanical product development. Wang began his career as a medical doctor and biomedical scientist at China Medical University and the Medical School of Nagasaki University, Japan. Later, he moved into industry and got involved in botanical product development in the U S. He specializes in product development strategy and planning, regulatory affairs and clinical project management. Wang is a certified medical writing professional (Center for Professional Innovation and Education), a certified clinical research professional (Society of Clinical Research Associates) and holds the Regulatory Affairs Certification. He can be reached at ericw@skingenix.us. Conclusion The pharmaceutical industry currently faces two major challenges: the increased cost of drug discovery and development, and drug affordability through the managed healthcare delivery system. FDA has opened the door to botanical products that offer significant potential and opportunities for the industry, despite limited experience on the part of manufacturers and the agency. Regulatory requirements and FDA s evaluations of botanical INDs are typically applied a case-by-case basis. Therefore, in addition to the Botanical Guidance, a pre-ind meeting and efficient communication with the agency are extremely helpful. The sponsor must scientifically justify safety and quality issues and provide an adequate rationale for proposed clinical studies. These issues need to be continuously re-evaluated and addressed along with the progress of clinical studies. From a business Regulatory Focus 41