Robin Ward07.01.02
Over five years ago, FDA published an advanced notice of proposed rulemaking (ANPR) on good manufacturing practices (GMPs) for the manufacture of dietary supplements. Although changes in the White House and Congress stymied progress toward compulsory GMPs designed to assure the safety and quality of dietary supplements in the U.S., a final ruling is expected in September this year. In Europe, the legislative environment has also been subject to review, with the national medicines agencies of the 15 member states working toward unified regulatory rules for dietary supplements and herbal medicines in the European Union (EU). The first wave of legislation, the Vitamins and Minerals Directive, has already been adopted into European law, and the focus is now on herbal medicines. While the FDA has focused on GMPs, effectively treating dietary supplements as foods, the roots of the EU's new legislation on herbal products clearly lie in existing European pharmaceutical legislation and standards.
From the outset, the U.K.'s Medicines Control Agency (MCA), a strong motivator behind the current legislative approach, and other national agencies were eager to establish a clear legislative category for herbal products in Europe and to resolve the disparity between legislation in the individual member states. In some national markets, such as Germany, France and Austria, herbal preparations are already well defined under existing laws. However, current laws in other markets, such as The Netherlands and the U.K., are less stringent or, at the very least, less well enforced.
The Traditional Herbal Medicines Directive is recognition by the EU that, because of their long tradition of use, a market will exist for herbal products whether legislated or not. The EU's approach is to establish a feasible regulatory control scheme by which the safety and quality-described by the EU Pharmaceutical committee as 'potentially hazardous products'-are monitored, instead of creating a "gray" market by banning the products completely. On the flip side, the EU also considers this a matter of consumer choice, stating that even if efficacy has not been fully established, consumers should be given the option of having access to the traditional medicines they trust.
Unlike the European Vitamins and Minerals Directive, in which the ingredients are treated more or less as foods albeit with specified maximum doses, the roots of the Traditional Herbal Medicines Directive can clearly be found in current European medicines law.
Current European medicine legislation is based on three pillars including the proofs of quality, safety and efficacy. The Traditional Herbal Medicines Directive amends the third requirement, proof of efficacy, and replaces it with the need to prove only tradition of use in relation to a specific condition. The first two pillars, quality and safety, remain largely unchanged, and will establish the standard for herbal products in Europe.
To understand both the thinking that underpins the Directive and its implications, it is easiest to look at the criteria that need to be met by an applicant for a product license. Although some of the detail and wording may change in the final Directive, the "horse trading" between member states has largely been concluded.
The standards for quality under the Traditional Herbal Medicines Directive leave no room for compromise as made clear in Article 3 of the Directive.
The application shall be accompanied by:
"The particulars and documents referred to in Article 4, paragraphs 1 to 10, of Directive 65/65/EEC, with the exception of the results of pharmacological and toxicological tests and the results of clinical trials as referred to in paragraph 8 of that Article. The summary of product characteristics need not contain the data specified in paragraph 4 of Article 4a of Directive 65/65/EEC."
The real implication of the above is that each product will need a robust quality file, including validated data for analysis and stability, and, if applicable, will also need to comply with designated EU monographs. The same quality requirements as non-traditional medicines will need to be met by traditional herbal medicines, including full pharmaceutical GMPs, a description of the method of preparation, a description of the control methods employed by the manufacturer, qualitative and quantitative analysis of the constituents and of the finished product, special tests (e.g., for the presence of heavy metals, stability, biological and toxicity) and controls carried out at intermediate stages of the manufacturing process. In essence, a full Drug Master File (DMF) will need to be provided, which will form part of the product license, and that will need to be updated on a regular basis.
The second pillar of the European medicines legislation is safety. The Traditional Herbal Medicines Directive simplifies this requirement, acknowledging that traditional herbal medicines have by their very definition a history of safe use. Product license applicants will be required to show bibliographic reviews of safety data and other sources of evidence, together with an expert report, but not the full range of tests and trials that accompany non-traditional medicine applications as proof of safety. However, where an authority considers it necessary for assessing the safety of a particular medicinal product, it may also require the applicant to present additional data. Pharmacovigilance will apply as for non-traditional medicines.
The third pillar of the European medicine legislation, efficacy, is best translated in the Directive as "tradition and plausibility of use." As with safety, tradition and plausibility of use can be established with reference to bibliographic review for the designated pathology, probably including at least one statistically valid double-blind cross-over trial. However, pathologies that require intervention by a medical practitioner are not permitted. In all cases there should be reasonable congruence between the defined strength and form (i.e., oral, inhalation, etc.) as per the application and cited studies. One of the main sticking points in the legislation is the definition of traditional use, with some industry commentators expressing concerns about the requirement to prove a tradition of use for the specified application of not less than 30 years in the EU for the claimed application (or 15 years inside the EU and 15 years outside it). This requirement could potentially lead to a rather short list of candidate ingredients and will almost certainly exclude almost all combination products.
Although an applicant will be able to present data for registration of any traditional herbal medicine, the EU will also plan a list of specific traditional herbal medicine products and monographs including therapeutic indication, specified strength, route of administration and information necessary for safe use. Once a monograph has been issued, all traditional herbal medicines, including the designated ingredient, will be required to comply with the monograph within 12 months of its adoption.
Unless an herbal product was grandfathered under the European Medicines Directive 65/65/EEC, label and advertising claims are currently strictly limited in the EU. Even the vague claims familiar in the U.S. market are not permitted in most member states. This is set to change, with medicines attaining a marketing authorization under the Traditional Medicines Directive potentially gaining a key marketing advantage with direct reference permitted to the specific traditional use to which the application pertained. As in the U.S., labeling and advertising will also require a qualifying statement to the effect that the product is a traditional use medicinal product for use in a specified indication. The labeling will be required to state that the efficacy of the product has not been clinically proven but relies exclusively on long-term use and experience, and that the user should consult a doctor if the symptoms persist during the use of the medicinal product.
The resource investment in registering an herbal under the Traditional Medicines Directive will be significant, so what will be the benefit for a company registering a tradition herbal medicine? Without a doubt one of the most significant upsides will be the possibility to make a direct function label claim, although the traditional claim might not be too distant from a health claim as a food. This should, however, give the licensed product a clear marketing advantage as it guarantees better information to consumers (a valid industry complaint under the current legislation in the U.S.), including adverse effects, instructions for use and clear information about the tradition of use underpinning the herb.
The consumer will also be a key beneficiary from the product quality requirement, providing assurance of content of active ingredients. This is not limited to the assurance of the quality of the raw ingredient as other data to establish registration (such as stability and dissolution data) will also be required. These items among others are sometimes overlooked by nutraceutical manufacturers, however, companies must keep in mind that they are key to ensuring the efficacy of a formulated product, which is why they form an essential part of main stream drug evaluation. Better quality, better formulation, safety controls, better information and the establishment of trusted brands should help to improve the public persona of herbal medicines and increase the public's confidence in the herbal medicines arena as a whole. Better consumer awareness may even act to raise the standards of manufacturing herbs and supplements marketed only as foods.
On the downside, the process of registration, formulation, stability testing, pharmaceutical GMPs, quality ingredients and validation data will have serious cost implications. As a result, consumers will have to bear the brunt of the selling price of traditional herbal medicines, which are likely to retail far above the selling price of current "food" or gray market equivalents. This may be the litmus test for the success or failure of the new legislation. It may also potentially be a sticking point for companies considering undertaking a traditional medicines application. It seems unlikely that the new legislation will chase the gray market products off the shelf in the short term, and when faced with "same" shelf low cost competition containing the "same" ingredient marketed as a food, companies considering registration may think twice. Some commentators in Europe doubt whether many companies will be willing to take on registration without greater market protection or policing of the gray market. There is a precedent for this in the Scandinavian market where a similar structure for traditional herbal medicine legislation already exists. In this region, the market position of some of the leading brands has been eroded in recent years by low cost supplements marketed as foods.
Another criticism of the legislation is that the 30 year rule will stifle innovation and prevent new ingredients from entering the market. In reality, the cost-driven philosophy of the nutraceutical industry is as much a barrier to development of new ingredients as any legislation. Currently, the nutraceuticals industry is largely a marketing-based industry building products based on the portfolios of ingredient manufacturers. Marketing companies package products, but generally do not develop new ingredients. The research required to uncover new ingredients and uses for herbal medicines requires investment, which provides some level of competitive advantage, or at least generates a level playing field, affords some market protection and grants sustainable margin to the ingredients developers. Of course, by definition new ingredients cannot be marketed under the umbrella of traditional medicine, and the EU will need to address this issue. The only current legislation is the Novel Foods regulation, which is expensive, rather tortuous and has been admitted by the EU to be largely unworkable in its current form. With so much technical knowledge inherent in Europe, resolution of legislation on new ingredients will be important for the new ingredient pipeline in both Europe and America.
The nutraceuticals industry, as we know it in the U.S., is less well developed in Europe but consumer interest has been growing fast. The hope is that the new legislation will provide a framework that could help the industry develop a solid quality base, build consumer confidence and avoid the boom and bust that characterized the post-DSHEA environment in the U.S., where consumer confidence has eroded. The new legislative arena in Europe presents an opportunity to establish branded products in one of the largest single markets. It also raises the quality bar for U.S. nutraceuticals companies already active in Europe.NW
About the author:
Robin Ward is the sales and marketing manager for Linnea SA, Locarno, Switzerland. He can be reached at rward@linnea-worldwide.com.
From the outset, the U.K.'s Medicines Control Agency (MCA), a strong motivator behind the current legislative approach, and other national agencies were eager to establish a clear legislative category for herbal products in Europe and to resolve the disparity between legislation in the individual member states. In some national markets, such as Germany, France and Austria, herbal preparations are already well defined under existing laws. However, current laws in other markets, such as The Netherlands and the U.K., are less stringent or, at the very least, less well enforced.
Why Legislate?
The Traditional Herbal Medicines Directive is recognition by the EU that, because of their long tradition of use, a market will exist for herbal products whether legislated or not. The EU's approach is to establish a feasible regulatory control scheme by which the safety and quality-described by the EU Pharmaceutical committee as 'potentially hazardous products'-are monitored, instead of creating a "gray" market by banning the products completely. On the flip side, the EU also considers this a matter of consumer choice, stating that even if efficacy has not been fully established, consumers should be given the option of having access to the traditional medicines they trust.
Unlike the European Vitamins and Minerals Directive, in which the ingredients are treated more or less as foods albeit with specified maximum doses, the roots of the Traditional Herbal Medicines Directive can clearly be found in current European medicines law.
Current European medicine legislation is based on three pillars including the proofs of quality, safety and efficacy. The Traditional Herbal Medicines Directive amends the third requirement, proof of efficacy, and replaces it with the need to prove only tradition of use in relation to a specific condition. The first two pillars, quality and safety, remain largely unchanged, and will establish the standard for herbal products in Europe.
To understand both the thinking that underpins the Directive and its implications, it is easiest to look at the criteria that need to be met by an applicant for a product license. Although some of the detail and wording may change in the final Directive, the "horse trading" between member states has largely been concluded.
The First Pillar-Quality
The standards for quality under the Traditional Herbal Medicines Directive leave no room for compromise as made clear in Article 3 of the Directive.
The application shall be accompanied by:
"The particulars and documents referred to in Article 4, paragraphs 1 to 10, of Directive 65/65/EEC, with the exception of the results of pharmacological and toxicological tests and the results of clinical trials as referred to in paragraph 8 of that Article. The summary of product characteristics need not contain the data specified in paragraph 4 of Article 4a of Directive 65/65/EEC."
The real implication of the above is that each product will need a robust quality file, including validated data for analysis and stability, and, if applicable, will also need to comply with designated EU monographs. The same quality requirements as non-traditional medicines will need to be met by traditional herbal medicines, including full pharmaceutical GMPs, a description of the method of preparation, a description of the control methods employed by the manufacturer, qualitative and quantitative analysis of the constituents and of the finished product, special tests (e.g., for the presence of heavy metals, stability, biological and toxicity) and controls carried out at intermediate stages of the manufacturing process. In essence, a full Drug Master File (DMF) will need to be provided, which will form part of the product license, and that will need to be updated on a regular basis.
The Second Pillar-Safety
The second pillar of the European medicines legislation is safety. The Traditional Herbal Medicines Directive simplifies this requirement, acknowledging that traditional herbal medicines have by their very definition a history of safe use. Product license applicants will be required to show bibliographic reviews of safety data and other sources of evidence, together with an expert report, but not the full range of tests and trials that accompany non-traditional medicine applications as proof of safety. However, where an authority considers it necessary for assessing the safety of a particular medicinal product, it may also require the applicant to present additional data. Pharmacovigilance will apply as for non-traditional medicines.
The Third Pillar-Efficacy
The third pillar of the European medicine legislation, efficacy, is best translated in the Directive as "tradition and plausibility of use." As with safety, tradition and plausibility of use can be established with reference to bibliographic review for the designated pathology, probably including at least one statistically valid double-blind cross-over trial. However, pathologies that require intervention by a medical practitioner are not permitted. In all cases there should be reasonable congruence between the defined strength and form (i.e., oral, inhalation, etc.) as per the application and cited studies. One of the main sticking points in the legislation is the definition of traditional use, with some industry commentators expressing concerns about the requirement to prove a tradition of use for the specified application of not less than 30 years in the EU for the claimed application (or 15 years inside the EU and 15 years outside it). This requirement could potentially lead to a rather short list of candidate ingredients and will almost certainly exclude almost all combination products.
The Working Mechanics: Specific List & Monographs
Although an applicant will be able to present data for registration of any traditional herbal medicine, the EU will also plan a list of specific traditional herbal medicine products and monographs including therapeutic indication, specified strength, route of administration and information necessary for safe use. Once a monograph has been issued, all traditional herbal medicines, including the designated ingredient, will be required to comply with the monograph within 12 months of its adoption.
The Working Mechanics: Labeling & Advertising
Unless an herbal product was grandfathered under the European Medicines Directive 65/65/EEC, label and advertising claims are currently strictly limited in the EU. Even the vague claims familiar in the U.S. market are not permitted in most member states. This is set to change, with medicines attaining a marketing authorization under the Traditional Medicines Directive potentially gaining a key marketing advantage with direct reference permitted to the specific traditional use to which the application pertained. As in the U.S., labeling and advertising will also require a qualifying statement to the effect that the product is a traditional use medicinal product for use in a specified indication. The labeling will be required to state that the efficacy of the product has not been clinically proven but relies exclusively on long-term use and experience, and that the user should consult a doctor if the symptoms persist during the use of the medicinal product.
The Highs, Lows &
Some Concerns
The resource investment in registering an herbal under the Traditional Medicines Directive will be significant, so what will be the benefit for a company registering a tradition herbal medicine? Without a doubt one of the most significant upsides will be the possibility to make a direct function label claim, although the traditional claim might not be too distant from a health claim as a food. This should, however, give the licensed product a clear marketing advantage as it guarantees better information to consumers (a valid industry complaint under the current legislation in the U.S.), including adverse effects, instructions for use and clear information about the tradition of use underpinning the herb.
The consumer will also be a key beneficiary from the product quality requirement, providing assurance of content of active ingredients. This is not limited to the assurance of the quality of the raw ingredient as other data to establish registration (such as stability and dissolution data) will also be required. These items among others are sometimes overlooked by nutraceutical manufacturers, however, companies must keep in mind that they are key to ensuring the efficacy of a formulated product, which is why they form an essential part of main stream drug evaluation. Better quality, better formulation, safety controls, better information and the establishment of trusted brands should help to improve the public persona of herbal medicines and increase the public's confidence in the herbal medicines arena as a whole. Better consumer awareness may even act to raise the standards of manufacturing herbs and supplements marketed only as foods.
On the downside, the process of registration, formulation, stability testing, pharmaceutical GMPs, quality ingredients and validation data will have serious cost implications. As a result, consumers will have to bear the brunt of the selling price of traditional herbal medicines, which are likely to retail far above the selling price of current "food" or gray market equivalents. This may be the litmus test for the success or failure of the new legislation. It may also potentially be a sticking point for companies considering undertaking a traditional medicines application. It seems unlikely that the new legislation will chase the gray market products off the shelf in the short term, and when faced with "same" shelf low cost competition containing the "same" ingredient marketed as a food, companies considering registration may think twice. Some commentators in Europe doubt whether many companies will be willing to take on registration without greater market protection or policing of the gray market. There is a precedent for this in the Scandinavian market where a similar structure for traditional herbal medicine legislation already exists. In this region, the market position of some of the leading brands has been eroded in recent years by low cost supplements marketed as foods.
Another criticism of the legislation is that the 30 year rule will stifle innovation and prevent new ingredients from entering the market. In reality, the cost-driven philosophy of the nutraceutical industry is as much a barrier to development of new ingredients as any legislation. Currently, the nutraceuticals industry is largely a marketing-based industry building products based on the portfolios of ingredient manufacturers. Marketing companies package products, but generally do not develop new ingredients. The research required to uncover new ingredients and uses for herbal medicines requires investment, which provides some level of competitive advantage, or at least generates a level playing field, affords some market protection and grants sustainable margin to the ingredients developers. Of course, by definition new ingredients cannot be marketed under the umbrella of traditional medicine, and the EU will need to address this issue. The only current legislation is the Novel Foods regulation, which is expensive, rather tortuous and has been admitted by the EU to be largely unworkable in its current form. With so much technical knowledge inherent in Europe, resolution of legislation on new ingredients will be important for the new ingredient pipeline in both Europe and America.
As a Framework Could it be the Way Forward?
The nutraceuticals industry, as we know it in the U.S., is less well developed in Europe but consumer interest has been growing fast. The hope is that the new legislation will provide a framework that could help the industry develop a solid quality base, build consumer confidence and avoid the boom and bust that characterized the post-DSHEA environment in the U.S., where consumer confidence has eroded. The new legislative arena in Europe presents an opportunity to establish branded products in one of the largest single markets. It also raises the quality bar for U.S. nutraceuticals companies already active in Europe.NW
About the author:
Robin Ward is the sales and marketing manager for Linnea SA, Locarno, Switzerland. He can be reached at rward@linnea-worldwide.com.
