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A Practical Guide to Licensing Herbal Medicinal Products

A Practical Guide to Licensing Herbal Medicinal Products by Thomas Brendler, L. Denzel Phillips, Stefan Spiess, Ann Godsell, and Birgit Wobst. London and Chicago: Pharmaceutical Press; 2009. Hardcover; 770 pages. ISBN 978-0853697848. $330.00

European Union markets for herbal products are currently undergoing dramatic changes. The industry is facing major problems with the authorization of health claims on food supplements with herbal ingredients by the European Food Safety Authority (EFSA). With the future of the botanicals in potential jeopardy, the members of the herb industry have started considering the possibility of using a process to re-categorize food supplements* with herbal ingredients into licensed drugs. One way of achieving this goal was been implemented into the EU drug legislation in 2004 in the form of the so-called “Traditional Herbal Medicinal Product Directive” (2004/24/EC), which has been included into the general drug legislation 2001/83/EC. The Traditional Herbal Medical Product Directive, or THMPD, allows for a simplified access to drug registration for traditionally used herbs and herbal ingredients, without the need of submission of clinical and preclinical data to support safety and efficacy, under certain conditions.

The EU botanicals industry has not fully risen to the occasion, and the transition deadline of April 30, 2011, is drawing closer—with potential consequences for the existing markets. Whereas EU member states such as the United Kingdom have already announced forthcoming regulation of unlicensed botanicals, other EU states (e.g., Italy, Portugal) do not seem to care about the upcoming deadline. This is also reflected in the numbers of granted licenses, which vary between none granted to date in many EU member states (and no applications pending) and at least 27 different herbs in at least 166 products approved in the UK.

To date, the THMPD cannot be considered as a success. Due to the restrictions in the registration process and the high financial burdens for the manufacturers in developing the required analytical standards, many manufacturers prefer to remain in the sector of food supplements and to undergo health claim applications with the EFSA as the less costly and apparently simpler access to markets. It remains to be seen what will happen after the end of the transition period. However, with a realistic timeframe from bench to registration of 3 years, it would now be too late to change the course for the already-existing botanicals in supplements.

The apparent apathy of both many members of industry and regulators may change in view of the de facto higher requirements on proof of efficacy for food supplements claimed by the EFSA as compared to traditional herbal medicinal product registration. This situation is likely to trigger a higher interest in the registration procedure, but the manufacturers coming from the food sector frequently feel helpless when it comes to the practicalities of herbal medicinal drug registration—even in the simplified form as traditional herbal medicinal products (THMP). The recently published Practical Guide to Licensing Herbal Medicinal Products may thus become a useful tool for companies considering the switch from the category of food supplement to registered medicinal product. In the following, the contents of the guide will be critically assessed from the point of view of an expert dealing with the practical application of herbal medicinal product licensing on a daily basis. The authors are highly knowledgeable in their respective fields, and the information given is accurate.

The Guide is organized into 8 chapters giving information on product eligibility, herbal raw material and herbal product quality, and the contents and internal organization of the Common Technical Document (CTD), that is, the dossier required for licensing.

The Guide starts with an introduction giving background information on why the THMPD was deemed necessary. It explains why the THMPD was introduced for simplified and less demanding access to the drug market. The requirement for such a regulation was mainly seen as a contribution to consumer protection. Marketing of herbal medicinal products under drug status involves stringent quality testing and should therefore avoid many of the adulterations and contaminations observed in the uncontrolled supplement sector.

Registration as a THMP has its restrictions: A tradition of 30 years of use must be demonstrated (15 of which must be within the EU), and the regulation is confined to herbs only (with the possibility to use ancillary quantities of vitamins or minerals). However, not even all herbs would be eligible, as they have to be compatible with oral or topical nonprescription drug use, i.e., without medical supervision. Moreover, when a given herb is well-researched, a registration as a THMP might not be granted, as in such cases the applicant would have to go through the regular marketing authorization process.

Chapter 1 (“Classification of Herbal Medicinal Products”) gives a valuable overview of potential herbal product classifications and provides a decision-tree allowing a quick check on which approach might be taken for a specific product, with a strong emphasis to the situation encountered in the UK. The reader must be aware that THMPs are purely national registrations; thus, the situation is almost completely different in other EU member states. Still, the basic differentiation between drugs, foods, and cosmetics is a more global one and applicable to other EU member states as well.

Chapter 2 (“Proof of Tradition”) gives information on how to find or use data on traditional application of herbal medicinal preparations. The references to overseas EU territories are highly interesting and open doors for unusual traditions. The chapter also provides ample reference to monographs which can be used for proofs of tradition. Unfortunately, the current practice of THMP licensing shows that the mere reference to such sources does not seem to be sufficient, as they merely provide information on the former existence of a given preparation, but not on the scope of actual use or availability on the market. The concept of proof of tradition is therefore still wide open to discussion.

Highly important is the reference to the work of the European Medicines Agency’s (EMA) Herbal Medicinal Product Committee and the so-called Community Monographs. These monographs will tremendously facilitate the proof of tradition, as the burden of proof will no longer be with the applicant. The Guide makes reference to 22 adopted monographs — fortunately for the potential applicant, there has been a further increase in published monographs since the Guide appeared (89 published, 74 of which were adopted on December 6, 2010). The downside, however, is that the list in the Guide does not differentiate between eligible and non-eligible plants.

A potential applicant should always check with the most recent list of monographs published on the website of the EMA (www.ema.

Chapter 3 (“Common Technical Document”) describes the contents and structure of the registration dossier. For those who do not already know the registration process, the information is not detailed enough to understand the underlying concept, and those who are familiar with the process will recognize that this chapter is an almost verbatim replication of existing official guidelines on the application of the “Common Technical Document” (CTD) format, without additional information. Even the expert will have to countercheck with the most recent version of this guideline published on the EMA’s website—a simple reprint of a potentially older version is therefore not useful. A more practical approach with explanations of the pitfalls with practical examples would have been more suitable.

Chapter 4 (“Good Agricultural and Collection Practice”) gives a good description of the backgrounds of herbal raw material quality required for drug registration—a topic that many companies selling herbal preparations apparently have never considered. Experience shows that information on the traceability of the herbal raw material and the quality issues related with the treatment of the plant from seeding to processing are more and more in the focus of regulatory authorities. This is with good reason, as the quality of herbal medicinal products is largely defined by the selection of a suitable source ensuring the absence of contaminants and adulterations, as well as sufficient levels of relevant analytical marker substances.

Chapter 5 (“Quality Requirements for Traditional Herbal Medicinal Products”) starts by giving details on legal definitions and guidelines. These guidelines, listed in Appendix 2, must not be considered as complete, as the EMA is constantly producing new guidelines, notes for guidance and Question and Answer papers on specific topics. In fact, the new EMA website provides a tool for the quick identification of the relevant regulations.

The quality requirements provided in this chapter are generic: They do not only refer to the special case of THMPs, but to herbal medicinal products in general. Basically, there is no difference in quality requirements between traditional and well-established herbs— which is also one of the reasons why so few applications have been filed. Going through the process of quality assurance is rather expensive, and in the case of combination products containing multiple herbal ingredients—for many traditional preparations, this is the rule rather than the exception—may become prohibitively costly. Still, the chapter is extremely important as it provides the background, information, and explanation the reader is missing in Chapter 3.

Chapter 6 (“Safety and Pharmacovigilance”) describes the data required for the compilation of safety data in the non-clinical and clinical parts of the CTD documentation. As the requirement for genotoxicity data has been introduced only after the implementation of the THMPD, the chapter on pre-clinical data puts special emphasis on genotoxicity testing. Again, the regulatory development is by now way past the point described by the Guide, which is based on EMA guidelines of 2007. Meanwhile EU regulatory authorities not only call for product-specific genotoxicity testing, regardless of data derived from bibliographic sources, but also call for a detailed justification of the observation of negative test results (whereas products with positive test results would stand little chance of being registered). Herbs are now generally considered as genotoxic, and if the testing does not confirm this, the applicant will have to explain why the test results did not confirm the suspected genotoxicity.

The Guide’s parts on pharmacovigilance shortly describe the requirements for periodic safety update reports (PSURs) post-registration—a task of which many potential applicants originally coming from the food sector are not aware. In fact, it appears important to strengthen the part on pharmacovigilance in future editions of the Guide. Pharmacovigilance does not only imply the collection of safety-related information and the periodic filing of such data, it also implies the creation of an infrastructure within the company to conduct such a process and to act on it when needed. Manufacturers coming from the food supplement sector may not be aware that a “Qualified Person responsible for Pharmacovigilance” (QPPV) is mandatory for every pharmaceutical company, and that the company needs to establish a “Pharmacovigilance System” with standard operation procedures (SOPs) in place, documented according to rules related to Good Manufacturing Practices (GMPs). These tasks go along with regular literature searches for newly published safety data, and the obligation to analyze and report potential cases within given time frames. Unfortunately, this topic is not presented in the Guide.

Chapter 7 (“Labelling”) describes the parts relating to the administrative information of Module 1 of a CTD for drug registration. These requirements are specific for every single EU member state. They are described in the Guide from the UK perspective. Some parts of the description are directly applicable to other EU member states as well, but adaptations must be made. The focus on UK regulations is also clear by the claim that all information in the package labeling and in the readability user test needs to be made in English. Of course, the information needs to be in the language of the EU member state, in some cases even in more than one language. This focus on the UK situation is found throughout the whole guide and makes the title A Practical Guide to Licensing Herbal Medicinal Products somewhat misleading, as the words “in the UK” are missing.

Chapter 8 (“Submission of THMP registration Applications – Frequently Asked Questions”) is again entirely focused on the submission in the UK. It briefly describes the possibility of obtaining scientific advice by the regulatory authorities, and quickly touches on questions related to manufacturers or distributers/importers licensing. It also provides a short introduction to electronic submission of parts of the licensing application. Similar regulations are in place in other EU member states, but it is highly advisable to check with the websites of the corresponding regulatory authorities before a submission is made—this also applies to the UK, as the details may change.

In conclusion, the Practical Guide to Licensing Herbal Medicinal Products provides valuable information for the background and practical problems of THMP licensing. From experience with non-EU companies trying to find their way into the European system, the information might still not sufficiently cover the main questions and problems the companies are facing. The Guide should also provide some ideas regarding realistic time schedules—many applicants are not aware that registration takes years until reaching a point where a product can be marketed, years during which the applicant has only expenses, but no return on investment.

The Guide is written from the perspective of experts familiar with the drug registration process, which explains why many questions regularly asked by non-experienced companies are not covered. For example, it would be preferable to more closely explain the key steps in product development, especially regarding the analytical processes and the galenical development, including validations. The information is there, but the key points deserve a more detailed explanation with a focus on typical traditional preparations, i.e. simple plant powder preparations or the specific problems with combinations of herbs for which there is no monograph.

The idea behind the Guide is good—but the oeuvre still needs updating, opening to the conditions in other EU member states, and to take into account the perspective of an unknowledgeable applicant completely overwhelmed by the regulations.

Who needs this book? Probably not those who are already familiar with drug licensing in Europe, especially in the sector of well-established herbs. For manufacturers unfamiliar with drug regulatory affairs it represents a useful introduction into the topic.

And, yet, there is one minor (or possibly major) drawback to this otherwise excellent resource: For some inexplicable reason, the publisher has issued this item in a 2-ring binder format. With the weight of about 6 pounds, the 2 binders simply cannot hold the pages together, and the pages pull the ring apparatus from the binder. Given the fairly significant price for this “book,” it is mystifying why the publishers would produce it in a format that would create inevitable problems and frustration for the intended buyer.

—Mathias Schmidt, PhD Director, HerbResearch Germany Tussenhausen-Mattsies, Germany

*The operative legal term is food supplement in Europe; the term dietary supplement was initially an American term, initiated with the passage of the the Dietary Supplement Health and Education Act of 1994.