Overview and update on EU directive 2004/24/EC: Traditional herbal medicines

Transcription

1 10 Herbal medicinal products Overview and update on EU directive 2004/24/EC: Traditional herbal medicines Author Greer Deal, Global Regulatory Services, Cambridgeshire, UK Keywords Traditional Herbal Medicinal Products Scheme (THMPS); MHRA; Committee on Herbal Medicinal Products (HMPC); Traditional Herbal Registration (THR) application; Traditional Chinese Medicine (TCM) Abstract By now, all regulatory affairs professionals will be fully aware of the European Directive on Traditional Herbal Medicinal Products (2004/24/EC), with some professionals being directly involved in the registration process. Many herbal companies, however, are new to what they believe is stringent legislation. These companies struggle to comply with their current staffing levels and with limited or no experience in regulatory affairs. As the April 2011 deadline draws ever closer, signalling the end of the transitional period for traditional herbal remedies to obtain registration, this article will attempt to identify what, if any, updates there have been since Regulatory Rapporteur featured traditional herbal medicines back in It also includes feedback from companies about the impact that the European Directive on Traditional Herbal Medicinal Products (2004/24/EC) has had on their businesses, along with their predictions for the future of the industry. To provide a balanced viewpoint, the MHRA was consulted via a telephone briefing, the results of which are recorded in this article. Background In March 2004 the European Directive 2004/24/EC was adopted and so the term traditional herbal medicinal product was established. The word traditional is key, as it is important to demonstrate that the herbal medicine or corresponding (ie, comparable) product(s) has been in traditional medicinal use for 30 years preceding the date of the application for the required medicinal indication. Fifteen years of this usage must have been within the EU. If these years of usage in the EU cannot be satisfied but the product(s) meets all the other requirements of the Directive, the health authority can refer the product(s) to the Committee on Herbal Medicinal Products (HMPC) which has the discretion to lower the requirement for 15 years use although there is no guarantee of this. So why regulate herbal remedies? Increasingly, consumers have turned to plant-derived remedies in the belief that these natural products are safer than conventional medicines. The words natural, herbal and plant-derived can be misleading and it is important for the public to be reminded that herbal remedies are medicines in their own right. Health authorities have been concerned about the safety profile and quality of such medicines for a number of years now. In some national markets, such as Germany, France and Austria, herbal preparations were already well defined under existing laws. However, laws in other markets, such as the Netherlands and the UK, were less stringent or, at the very least, less well enforced. So EU Directive 2004/24/EC was implemented in order to harmonise the regulations, enable the free movement of herbal products within Europe and protect the consumer. We must remember that many pharmaceutical medicines are derived from plants based on the powerful compounds they contain. In addition, just because a remedy is herbal doesn t mean a consumer won t suffer side-effects or adverse events. It is also important to bear in mind possible interaction between herbal medicines and other medicines which could result in a reduced or enhanced effect of either medicine. For example, it is well known that St John s Wort interacts with SSRIs and oral contraceptives. It is understood that the more stringent regulation of traditional herbal remedies, via this EU Directive, will help health authorities achieve and maintain their key objective to protect the consumer. Key requirements of the Traditional Herbal Medicinal Products Scheme (THMPS) 1 Ascertain classification of the herbal product. This may seem to be stating the obvious. Herbal products, however, aren t necessarily traditional herbal remedies and their classification can often be determined by the overall strategy of the company producing the remedy. For example, classification as a medical device (eg, ear drops, skin patches) may be possible and more desirable: registration is generally quicker and therefore, a company s return on investment (ROI) will be much sooner than via the traditional route. Other possible routes to market are as: l Food (functional food, novel foods regulation, dietary food for special medical purpose, PARNUTS, food supplement) l Cosmetic l Medicine for human use (well established use, full Marketing Authorisation) l Veterinary product. The MHRA has helpfully published a Herbals Roadmap on its website to help companies determine whether or not their product is a traditional herbal remedy and therefore needs registration. 2 2 Safety. This is where regulatory professionals can plainly see the simplification of the registration requirements for a traditional herbal remedy compared with a conventional pharmaceutical medicine. In this instance Module 4 of the Common Technical Document (CTD) requires bibliographical evidence on safety (including cross-referencing to the appropriate Expert Report) and therefore replaces the usual nonclinical study reports. If, however, the herbal substance is included on the Community List 3 there is no need to provide a safety summary. If a safety summary is required it must consider: l All herbal ingredients (+ vitamins or minerals) l Use in pregnancy and lactation etc l Potential interactions with other medication, herbal products and/ or food.

2 Herbal medicinal products 11 When the THMPS was enforced, many companies were blissfully unaware that they were required to undertake pharmacovigilance activities (another added expense). In fact, in the early days, the MHRA s website made no reference to this requirement! 3 Confirm traditional use of the product. As with safety, this is a key part of the CTD for traditional herbal medicines and consists of bibliographical evidence. It replaces the usual requirement of clinical studies in Module 5, although if studies are available these should be included. So what is meant by traditional? Put simplistically, it is a herbal product which is: l Intended and designed for use without the intervention of a medical practitioner for diagnosis, prescription or monitoring of treatment l Taken orally, for external use or inhalation l The efficacy must be plausible on the basis of long-standing use and experience. Acceptable sources of evidence include: l Information from handbooks of medicine, pharmacology, pharmacy, phytotherapy, herbal medicine, pharmacopoeia l Official expert committee reports, ESCOP monographs l Product-related documentation (eg, product brochures) l Company archive materials (eg, sales invoices). 4 Quality. Even if the herbal substance is included on the Community List, 3 quality must still be demonstrated. Quality applies from the Field to Finished Product, with key elements being adherence to Good Agricultural and Collection Practice (GACP) and Good Manufacturing Practice (GMP). Herbal products must contain the correct ingredients of acceptable quality, free from unacceptable contamination, and the claimed shelf life of the product must be supported. The normal quality requirements applicable to licensed medicines apply. There is also a requirement to hold a manufacturer s licence, a wholesale dealer s licence or a wholesale dealer s (import) licence where appropriate. Quality appears to be the most challenging aspect of registration, with examples of products from India and China using different genus of a plant for different batches of the same herbal remedy! 5 Labels and Leaflets Readability/User Testing (Directive 2001/83/ EC). The package leaflet shall reflect the results of consultations with target patient groups to ensure that it is legible, clear and easy to use. 4 The aim of a readability test is to demonstrate that patients can: l Locate information in the PIL l Understand it l Know how to act on it. The product labelling and leaflet must include the statement: Product X is a traditional herbal medicinal product for use in specified indications exclusively based on longstanding use. And the correct certification registration mark must be used (go to for a visual image). The MHRA explains: The certification mark has been designed as an additional visible symbol to help consumers more easily distinguish those products benefiting from a THR from those which do not. 6 Advertising. Specific advertising requirements 5 apply to THMPs over and above other provisions and specific extra wording on advertisements of THMPs is required: Traditional herbal medicinal product for use in (registered indication) exclusively based upon longstanding use as a traditional remedy. Enactment, however, has been delayed until 20 April Article 16d. 6 It is possible to obtain mutual recognition of the registration of a herbal medicine in the EU. Article 16d of Directive 2004/24/EC (as amended) outlines that: l Mutual recognition shall apply to registration if covered by a Community Herbal Monograph l The herbal ingredient is recorded on the Community List l Member states must take into account registration by other member states. Interestingly, the MHRA s only experience with registrations to date is at national level and as yet no companies have taken advantage of the mutual recognition procedure. The MHRA believes this will happen in time as companies gain confidence and experience with the registration procedure. Updates and news applicable to the THMP Directive since June 2008 (over and above amendments to general marketing authorisation applications) are shown in Tables 1 and 2. Feedback from the herbal industry Through contacts made via direct enquiries and trade shows, examples have been gathered of some of the comments made by representatives of the herbal industry: l...hope it ll all go away l It ll never be enforced and there will be a change of heart at the eleventh hour l Come April 2011 we will close our doors and are currently looking for alternative revenue streams l We re working hard at registering our products but it is extremely time-consuming and expensive so we have to choose which products will or won t be registered l It s fairly straightforward to register single herb products but multi-combinational products are impossible under the THMPS and we definitely can t afford the time or money to obtain full product licences for them. Interestingly, and rather worryingly, some non-western companies believe they can bring their traditional remedies into Europe under the guise of a traditional herbal remedy even though their products, strictly speaking, are not herbals (see below for the MHRA s response). An informal poll carried out during the Botanicals Session at Genesis 2009 (the leading biotech networking event in Europe) asked if delegates thought the THMPD was a threat, an opportunity, or a necessary evil. No one saw it as a threat, unsurprisingly because of the entrepreneurial focus of the meeting; about half of the audience saw it as an opportunity; a handful as a necessary evil and the remainder abstained. The opportunities were cited as: l Perception of healthy. Herbal remedies are perceived by the consumer as natural and safe and, therefore, must be healthy. With regulation, this perception is reiterated, supported and enhanced, which could increase market share. l Recorded information. With regulation comes a requirement for more evidence to support applications. This in itself will result in a greater pool of evidence to further enhance our understanding of the benefits and actions of traditional herbal remedies. l Educational tool. Conventional doctors and consultants may now be encouraged to offer patients traditional herbal medicines as they will have information to hand on the safety profile of these products. l Increase in choice. Regulation may increase choice because conventional doctors and consultants will have the information and, therefore, the confidence to offer their patients herbal remedies to complement or perhaps even replace existing treatments.

3 12 Herbal medicinal products Table 1: European Medicines Agency updates Title Reference number Document date Reflection paper on the reasons and timelines for revision of final Community herbal monographs and Community list entries EMEA/HMPC/326440/08 04 Sep 2008 Procedure for calls for scientific data for use in HMPC assessment work EMEA/HMPC/1004/2006 Rev 2 12 Mar 2009 Procedure for the appointment by the HMPC of a Rapporteur responsible for: l A scientific evaluation l The establishment of a Community herbal monograph and/or Community list entry Establishment of Community herbal monographs and Community list entries and related documents EMEA/HMPC/108877/05 Rev 1 12 Mar 2009 SOP/H/ May 2009 Compiling scientific data to support HMPC assessment work SOP/H/ May 2009 Recommended format for a list of references supporting an assessment report EMEA/HMPC/574496/08 Rev 1 24 Jul 2009 Template for a Community herbal monograph EMEA/HMPC/107436/05 Rev 4 24 Jul 2009 Procedure on management of proposals from interested parties for Community list entries or Community herbal monographs EMEA/HMPC/328575/07 Rev.1 12 Nov 2009 Updated inventory of herbal substances for assessment EMEA/HMPC/494079/07 07 Apr 2010 Updated overview of HMPC assessment work priority list EMEA/HMPC/278067/06 07 Apr 2010 Glossary on herbal teas EMA/HMPC/5829/ Apr 2010 Community Monographs list now comprises of 75 documents: l 53 finalised l 22 under preparation Community List: l Six herbs have been formally adopted l Three herbs have been added to the list and are awaiting a final Commission Decision n/a April 2010 n/a April 2010 l Improvement in quality and safety. This has been a major concern and is a key reason why the Directive came into existence. There have been reports of herbal medicines containing potentially dangerous and even illegal substances such as lead, mercury and arsenic. Regulation should prevent this. l Improved public confidence. Research undertaken on behalf of the MHRA showed 77% of adults agreed it is important that herbal medicines are regulated. With herbal products having to comply with certain legal requirements, confidence and use of herbals could increase. l Robust product. An increase in supporting data and compliance in terms of quality and safety will result in a more robust product. This could have a positive effect on a company s profits. Compare these opportunities with the audience at the Natural & Organics Europe Show and, understandably, there is a marked difference in response. The majority see it as a threat for the following reasons: l Lack of choice for the consumer. It is predicted that out of 3,000 herbal remedies available on the UK market, only 300 will be registered by April 2011 this is a best case scenario. l Monopolies. Lack of choice will result in a few large companies monopolising the market. l Loss of tradition. Companies are finding that registration of their herbal products is cost-prohibitive and so the remedy (and therefore, tradition) will be lost forever. l Increased costs. Compliance with the Directive doesn t consist only of compilation and submission of a dossier, it also includes: GMP, GACP, pharmacovigilance, licence fees, package leaflet readability testing etc. Herbal companies can see only spiralling costs and many believe their companies will no longer be viable and so are looking for alternative revenue streams. l Inappropriate assessors. There is a perception that the assessors of herbal remedies are not appropriately qualified. This, however, is incorrect. For example, Dr Jidong Wu, recently reappointed to the Herbal Medicines Advisory Committee, is a traditional Chinese medicine (TCM) practitioner and senior lecturer in TCM at Middlesex University. 7 l Amendment to Article This indicates that in cases of doubt and where the definition of a medicine applies even if the product is already covered under other aspects of EU legislation (eg, foods), medicinal classification has supremacy. So whether a company perceives the Directive as an opportunity or a threat is very much dependent on if it has a pharmaceutical or natural product background and is used to regulation or not, as the case may be. Overall the herbal industry believes that choice and therefore

4 Herbal medicinal products 13 Table 2: Medicines and Healthcare products Regulatory Agency updates News/Update Volume 9A of The Rules Governing Medicinal Products in the European Union Guidelines on Pharmacovigilance for Medicinal Products for Human Use. Effective date September 2008 The review and transfer of certain herbal product licences (marketing authorisations) to traditional herbal registration status. 25 March 2010 Ipsos MORI report shows that 77% of adults agree it is important that herbal medicines are regulated. Research conducted on behalf of the MHRA. Guidance on the review of herbal product licences (marketing authorisations) to ensure that the herbal products are in the appropriate regulatory category. New section added to website to provide guidance and information on the transfer of herbal marketing authorisations to traditional herbal registration status. January 2009 January 2009 March 2009 Draft guidance on consumer advertising for registered traditional herbal medicines. April 2009 Report released on outcome measures used in relation to the MHRA s strategy for bringing herbal medicines into effective regulation. May 2009 Introduction of the Traditional Herbal Registration certification mark. October 2009 Final copy of the guidance on THR advertising to consumers Registered Traditional Herbal Medicines: Guidance on Consumer Advertising. April 2010 Table 3: Cumulative total of THR applications and grants since June 2008 By March 2009 By 23 March 2010 By 21 May 2010 All THR applications All THR grants No of applicants 30 No of applicants with one or more THRs 18 No of herbs included 53 tradition will be lost forever after April Many have said they will stop supplying herbal remedies and some are even going as far as winding up their businesses. Feedback from the MHRA, however, is more positive. MHRA feedback and update The MHRA is pleased with the number of applicant companies and Traditional Herbal Registration (THR) applications being made. As can be seen from Table 3, 30 different applicant companies have applied for THRs with 18 of these companies already having at least one THR granted. The MHRA feels that this represents a broad-based market. With regard to TCMs being registered as a traditional herbal remedy in Europe, the MHRA commented: The basic position is that if you re trying to put a manufactured herbal medicine on the market, whether a TCM, Ayurvedic or Western herbal, the basic rules are the same. So from next April if a company is wanting to put a manufactured herbal medicine of any kind onto the market it will need a suitable product licence or traditional herbal registration. We do recognise there are particular issues with TCMs (for example, evidence of traditional use in the EU) and this can be problematic for some products. There are, in fact, a number of other issues which in some ways can be greater stumbling blocks. For example, there is a requirement for certain quality standards (Good Manufacturing Practice) and certainly, in our experience with some TCMs on the UK market, quality is way short of that [GMP] in some cases. Then there is also the issue of some TCMs wanting to include much more potent ingredients than would be permitted under the THMRS or making much stronger claims than would be permitted. We in fact have always taken the view that in practice, although there may well be in time a modest scattering of TCMs which do get a traditional herbal registration, in fact much of this market is more relevant to the practitioner sector because many unlicensed TCMs are supplied by practitioners and clinics. On that issue we await a final decision on the regulation of practitioners. At the beginning of April the [then] Secretary of State announced a provisional intention to bring practitioners into the regulation. Obviously after the election we ll have to see whether that outline plan could be progressed by any new ministers. If that arrangement goes ahead, potentially this would offer a regulatory route for Traditional Chinese Medicine. Just over a year ago a review of the MHRA was conducted against the Hampton principles. 9 The resulting report confirmed that the MHRA has given companies a great deal of help in preparing for the Herbal Directive. It is believed that the extent of help and advice provided by other member states varies widely. The MHRA, however, continues to receive positive feedback from those companies that are operating across Europe and therefore, working with a number of different regulators.

5 14 Herbal medicinal products April how will the Directive be enforced? The MHRA has confirmed that: Over the summer, autumn and winter of this year we will be undertaking an information-gathering exercise identifying companies and products on the UK market which might be subject to the change next year, and we will then be corresponding with those companies so that they are fully aware of what s happening. Then from April 2011 it will be a mixture of checking and responding to complaints. After 30 April 2011 no further stock of unlicensed product can be sold. Stock already on retail shelves (ie, not with wholesalers or manufacturers) will be able to remain on the market until sold. Products with THR applications in hand at 30 April 2011 (but registration not granted), technically, will have to be removed until the THR is granted. The MHRA will be in dialogue with companies going through the procedure. For the foreseeable future companies will still be able to seek free-of-charge regulatory advice from the MHRA in the form of workshops, company-specific meetings and Q&As via trade associations. It is clear that the herbal industry will be policed and the Herbal Directive will be enforced. The UK has allowed the maximum time possible for the transitional period in order to help, educate and support herbal companies understand and comply with the requirements. This support is likely to continue after April 2011 but is somewhat dependent on the incoming government. It is also worth noting that the Hampton Review, however, recommends that this shouldn t continue indefinitely. 9 To those companies who believe the Traditional Herbal Directive will never be enforced and there will be a change of heart at the eleventh hour, the message from the MHRA is clear: April 2011 isn t going to go away. Acknowledgements 1 London Biotechnology Network, Platinum Sponsors of Genesis Colleagues working within the EU herbal industry. 3 The MHRA, especially: The Press Office (Market Towers, London); David Carter (Section Manager, Medicines Borderline Section) and Richard Woodfield (Head of Herbal Policy). References 1 Regulatory Rapporteur, Vol 5, No 6, June MHRA. Traditional Herbal Medicines Registration Scheme: Guidance for Retailers, Wholesalers, Importers and Manufacturers on the Requirements of the THMRS, p3. 3 Community List. 4 Title V of Council Directive 2001/83/EC (as amended), Article 59(3). 5 SI 541 of 2007 Medicinal Products (Control of Advertising) regulations. 6 Article 16d of Directive 2004/24/EC of the European Parliament and of the Council of 31 March 2004 amending, as regards traditional herbal medicinal products, Directive 2001/83/EC on the Community code relating to medicinal products for human use. 7 MHRA (press release). Appointment to the Herbal Medicines Advisory Committee, 15 March Article 2.2 of Directive 2001/83/EC as amended by Directive 2004/27/EC. 9 MHRA. A Hampton Implementation Review Report. WORKSHOPS Training designed with you in mind TOPRA The Organisation for Professionals in Regulatory Affairs Ref: CMC 1 2 CRED: CMC - Drug Substance and Medicinal Product The Evolving Pharmaceutical Dossier Day 1 Drug Substance Course content Information on the latest scientifi c and technical updates and/or requirements An insight into the data requirements and common regulatory issues for Drug Substances including an overview of the Drug Master File (DMF) and EU Certifi cate of Suitability procedures; use of pharmacopoeial monographs; issues often faced at different phases of development concerning specifi cations, production, validation, stability; ICH regional requirements; Active ingredient manufacturer inspections: other current issues; ICH Q11; Variations A Regulatory Authority s perspective on how to get it right fi rst time including potential pitfall areas; what makes a good quality summary; practical issues in the presentation of Marketing Authorisation applications. Also available as a one day course. Ref: CMC-1 Day 2 Drug Product Course content An insight into the data requirements and common regulatory issues for Drug Products including an outline of the issues often faced at different phases of development such as specifi cations, production, validation, stability; specifi c data requirements for and issues associated with different dosage forms; ICH regional requirements, other current issues; ICH Q11; Variations A Regulatory Authority s perspective on how to get it right fi rst time including potential pitfall areas; what makes a good quality summary; practical issues in the presentation of Marketing Authorisation applications. Also available as a one day course. Ref: CMC-2 Date: October 2010 Venue: Radisson SAS Portman Hotel, London, UK CRED CMC 12hrs * Lifelong Learning *For more information please visit / lifelonglearning