Market Towers 1 Nine Elms Lane London SW8 5NQ Tel: 020 7084 2068 Fax: 020 7084 2387 E mail:[email protected]To: Interested organisations 29 January 2004 Dear Sir or Madam CONSULTATION LETTER MLX 296: PROPOSALS TO PROHIBIT THE SALE, SUPPLY OR IMPORTATION OF UNLICENSED HERBAL MEDICINAL PRODUCTS FOR INTERNAL USE WHICH CONTAIN SENECIO SPECIES. 1. Please find the attached consultation document MLX 296. You are invited to consider and comment upon the proposals set out in the document including the draft Partial Regulatory Impact Assessment. 2. The consultation document MLX 296 contains: A summary and the background to the proposal The proposal A draft partial Regulatory Impact Assessment (RIA) A draft Order A reply form. A list of organisations being consulted
CONSULTATION LETTER MLX 296: PROPOSALS TO PROHIBIT THE SALE, SUPPLY OR IMPORTATION OF UNLICENSED HERBAL MEDICINAL PRODUCTS FOR INTERNAL USE WHICH CONTAIN SENECIO SPECIES.
1. Please find the attached consultation document MLX 296. You are invited to consider and comment upon the proposals set out in the document including the draft Partial Regulatory Impact Assessment.
2. The consultation document MLX 296 contains:
A summary and the background to the proposal
The proposal
A draft partial Regulatory Impact Assessment (RIA)
A draft Order
A reply form.
A list of organisations being consulted
3. Should you have any questions regarding the proposals or the conduct of the consultation exercise, please contact Judith Thompson (Tel: 020 7084 2945, Email: [email protected]).
Background...................................................................................................................3Senecio.............................................................................................................................................3Regulation of medicines containing Senecio species in the United Kingdom.................................4
The risk to consumer health.........................................................................................4
Recent Action in the UK................................................................................................5
The proposal..................................................................................................................5
Herbal medicines affected by the proposal...................................................................6
Other exceptions............................................................................................................6
Other options considered..............................................................................................6
Publication of comments...............................................................................................7
DRAFT PARTIAL REGULATORY IMPACT ASSESSMENT
Purpose and intended effect of the proposal................................................................................8Issue:.......................................................................................................................................8Objective:................................................................................................................................9
Quantifying and valuing the options....................................................................................11Issues of equity or fairness..........................................................................................................13Benefits identified and quantified...............................................................................................13Compliance costs for business.....................................................................................................14
Business sector affected........................................................................................................14Recurring costs, Non recurring costs and Total Compliance Costs.....................................14
Small firms impact test................................................................................................................15Competition assessment...............................................................................................................15Consultation..................................................................................................................................15Summary and recommendations................................................................................................16Enforcement, sanctions, monitoring and review.......................................................................16
APPENDIX A – Toxicity of unsaturated pyrrolizidine alkaloids (PAs).................................17ANNEX B – draft Statutory Instrument....................................................................................20ANNEX C – Reply form...........................................................................................................24ANNEX D – distribution list.......................................................................................................25
PROPOSALS TO PROHIBIT THE SALE, SUPPLY OR IMPORTATION OF UNLICENSED HERBAL
MEDICINAL PRODUCTS FOR INTERNAL USE WHICH CONTAIN SENECIO SPECIES
Summary
1. In March 2002 it came to the attention of the Medicines and Healthcare products Regulatory Agency (MHRA) that a Chinese medicinal product, Qian Bai Biyan Pian, which traditionally contains the toxic plant Senecio scandens, had been placed on the UK market. Senecio scandens is a member of the plant genus Senecio. Species of plants within this genus contain unsaturated pyrrolizidine alkaloids (PAs) which are known to cause serious liver damage, known as veno-occlusive disease in man which can ultimately lead to the need for a liver transplant and/or death. Unsaturated pyrrolizidine alkaloids have also been shown to be carcinogenic, mutagenic and genotoxic in animals.
2. In response to the risk to public health posed, the MHRA wrote to all herbal interest groups on 26 March 2002 highlighting the toxicity of the genus and requesting a voluntary withdrawal of all unlicensed medicines which may contain Senecio species. However, the Agency has recently received a number of reports indicating that unlicensed herbal remedies which may contain Senecio continue to be supplied to the public.
3. In the interest of public safety, the MHRA is proposing that an order should be made under Section 62(3) of the Medicines Act 1968 to prohibit the sale, supply or importation of unlicensed medicinal products containing Senecio species, except in relation to those for external use. This proposal is the subject of this consultation document. A decision on whether to progress the proposal will only be made after careful consideration by Ministers of the responses to this consultation and advice from the Committee on the Safety of Medicines (CSM).
4. The proposals are set out below in more detail. A draft partial Regulatory Impact Assessment (RIA) is attached at Annex A and the draft order can be found at Annex B. Views on the proposals and the draft partial RIA are invited and responses should be submitted to the MHRA using the enclosed reply form at Annex C by Friday 23 April 2004. We will assume that your comments can be made publicly available unless you indicate on the form that you wish all or part of them to be treated as confidential.
Background
Senecio
5. Senecio is a plant genus of the family Asteraceae (Compositae). The plants within this genus are also referred to as the Ragworts. Senecio species contain unsaturated pyrrolizidine alkaloids (PAs) which are toxic, such as senecionine,
seneciphylline, retrorsine and jacobine. The unsaturated PAs are known to cause serious liver damage (hepatoxicity) resulting in veno-occlusive disease of the liver in man and can ultimately lead to the need for liver transplants and/or death. They have also been shown to be carcinogenic, mutagenic and genotoxic in animals.
Regulation of medicines containing Senecio species in the United Kingdom
6. As with other herbal medicines, there are two regulatory routes by which herbal medicines containing Senecio species can reach the UK market:
as unlicensed herbal remedies (through an exemption from licensing under section 12 of the Medicines Act), which are the subject of this consultation exercise.
as licensed herbal medicines.
7. Due to the established toxicity of Senecio species, one member of the genus, Senecio jacobaea L. is included in Parts II and III of the Schedule to the Medicines (Retail Sale or Supply of Herbal Remedies) Order 1977 (SI 1977/2130). This restricts the sale or supply of Senecio jacobaea in unlicensed herbal remedies to pharmacies, other than preparations for external use at concentrations below 10%. The restriction reflects the knowledge of use of Senecio at that time. This does not necessarily imply that the use of other Senecio species was considered acceptable on public health grounds in the mid to late 1970’s.
The risk to consumer health
8. Prior to March 2002, the Agency was not aware of the supply of unlicensed herbal remedies containing Senecio species.
9. However in March 2002 the MHRA became aware through correspondence from a General Practitioner that a Chinese medicinal product, Qian Bai Biyan Pian, which traditionally contains, and was labelled as containing, the plant Senecio scandens, had been placed on the UK market.
10. A monograph setting out the formulation for Qianbai Biyan Pian is included in the current Chinese Pharmacopoeia. The monograph lists seven herbal ingredients one of which is Senecio scandens. The product is indicated for acute or chronic rhinitis, nasosinusitis and pharyngitis.
11. In response to the risk to public health posed, the MHRA wrote to all herbal interest groups on 26 March 2002 highlighting the toxicity of the genus and requesting a voluntary withdrawal of all unlicensed medicines which may contain Senecio species. The Agency specifically asked to be made aware of any herbal interest groups that disagreed with its initial safety assessment or proposed not to advise its members to remove any relevant products from sale. No such representations were received. However, the Agency has recently received five reports from members of the public indicating that unlicensed herbal remedies
which may contain Senecio continue to be supplied to the public from a number of outlets across the UK.
12. To date, there have been no formal reports of adverse reactions in the UK associated with the use of Senecio through the MHRA’s Yellow Card reporting scheme.
13. In 1992, the European Union’s Committee on Propriety Medicinal Products (CPMP), compiled guidance in the form of a list of herbal drugs considered to present a serious risk to health, including herbal ingredients withdrawn for safety reasons in the European Community. The CPMP list includes all Senecio species, and states the reason for inclusion as “contains pyrrolizidine alkaloids with genotoxic, carcinogenic and hepatoxic properties”.
14. The UK has requested information from other Member States about any existing controls in their territories regarding the availability of products containing Senecio species. All of the ten Member States that have responded to date have measures in place to control the availability of Senecio in medicines.
Recent Action in the UK
15. Following the recent reports of the continued supply of Qian Bai Biyan Pian, the MHRA wrote on 1 October 2003 to the herbal sector requesting that unlicensed herbal medicines containing Senecio be removed from the supply chain. Recent reports have not been restricted to a single outlet or geographical region. Where possible, the Agency also sought and received reassurances from the clinics implicated in the recent supply of Qian Bai Biyan Pian that they would remove any relevant products from their shelves. However, it is possible that the product may have appeared at other outlets without the Agency’s knowledge or that Senecio species are being supplied in other unlicensed medicines which the MHRA is not aware of. On the basis of the available evidence, the MHRA considers any continued supply of Senecio in unlicensed medicines for internal use poses a serious risk to public health.
The proposal
16. In the interests of public safety, this document consults on a proposal to make an order under section 62 of the Medicines Act 1968 to prohibit the sale, supply and importation of unlicensed medicinal products containing Senecio species, other than products which are for external use only.
17. The test to be satisfied for such an order to be made is that it is necessary in the interests of safety. Efficacy is not primarily relevant but any information on efficacy can be taken into account.
18. The proposal affects all unlicensed herbal remedies for internal use which are on the UK market under section 12 of the 1968 Medicines Act and which consist of or contain any;
part of any plant from the Senecio genus, and/or
extract prepared from any plant from the Senecio genus.
19. Unlicensed herbal remedies available over-the-counter (OTC) and those supplied following a one to one consultation, between a member of the public and a herbalist or doctor for example, are covered by the proposal irrespective of dosage, strength etc.
20. The evidence that Senecio species are harmful relates only to internal use. In the interests of proportionality therefore, this proposal does not affect unlicensed herbal remedies which are for external use only.
21. This proposal does not affect any medicinal product containing Senecio which holds a marketing authorisation (product licence), or registered homoeopathic medicines. Separate consideration is being given to such products.
Other exceptions
22. In addition to the exceptions for licensed products and for remedies solely for external use, the prohibition would not apply to:
the sale or supply to, or importation by or on behalf of, a person exercising functions in relation to the enforcement of food or medicines legislation,
the importation from a European Economic Area (EEA) State, if the product in question originates from such a state or originates outside the EEA but is in free circulation in Member States (within the meaning of Article 23.2, when read with Article 24, of the EC Treaty), and is for re-export to another EEA State, rather than the UK market.
Other options considered
23. The Agency has considered a number of other options besides the proposal for prohibition of Senecio species in unlicensed medicines. These options are set out in the draft partial Regulatory Impact Assessment (RIA) and comments on those possible alternative measures are invited as part of the consultation exercise.
Timetable
24. The consultation period will close on Friday 23 April 2004.
25. If, after careful consideration of stakeholders views, and the advice of the CSM (and Medicines Commission where necessary), Ministers consider the proposed prohibition to be necessary in the interests of safety, the prohibition order will be made as soon as possible.
Publication of comments
26. To help informed debate on the issues raised by this consultation exercise, and within the terms of the Code of Practice on Access to Government Information (“Open Government”), the Agency intends to make publicly available a summary of responses received to this consultation.
27. The Agency’s Information Centre at Market Towers will supply copies of the results of the consultation on request. Copies may be further reproduced. An administrative charge, to cover the cost of photocopying and postage, may be applied.
28. We will assume that your comments can be made publicly available in this way unless you indicate on the reply form that you wish all or part of them to be treated as confidential and excluded from this arrangement. Under the Code of Practice on Access to Government Information, the Agency will not release confidential replies or replies containing personal confidential information.
29. Should you have any questions regarding the proposals or the conduct of the consultation exercise, please contact Judith M. Thompson (Tel: 020 7084 2945, Email: [email protected]).
30. If you consider there are other organisations that should be invited to comment on these proposals, please either pass a copy of the documents to them or contact the MHRA and we will arrange for a consultation pack to be sent to them.
– for proposals to prohibit the sale, supply or importation of unlicensed herbal medicinal products for internal use which
contain Senecio species
Purpose and intended effect of the proposal
Issue:
1. In March 2002, the Medicines and Healthcare products Regulatory Agency (MHRA) became aware of the supply of an unlicensed Chinese medicine, Qian Bai Biyan Pian, which traditionally contains the toxic plant Senecio scandens.
2. Senecio scandens is a member of the Senecio plant genus. Plant species within this genus are known to contain unsaturated pyrrolizidine alkaloids (PAs), which injure the liver in humans giving rise to serious liver damage. Unsaturated pyrrolizine alkaloids are known to cause serious hepatoxicity resulting in veno-occlusive disease of the liver in man and can ultimately lead to the need for a liver transplant and/or death. They have also been shown to be carcinogenic, mutagenic and genotoxic in animals.
3. In response to the risk to public health, the MHRA wrote to all herbal interest groups on 26 March 2002 highlighting the toxicity of this plant genus and requesting a voluntary withdrawal of all unlicensed medicines which may contain Senecio species. The Agency specifically asked to be made aware of any herbal interest groups that disagreed with its initial safety assessment or proposed not to advise its members to remove any relevant products from sale. No such representations were received, although a number of replies indicated support for the action taken.
4. Despite the voluntary withdrawal, the Agency has recently received five separate reports from members of the public indicating that unlicensed herbal remedies which may contain Senecio are again being supplied to the public. The reports have not been restricted to a single outlet or geographical region.
5. In the Agency’s view, any continued supply of Senecio species in unlicensed herbal medicines for internal use poses a serious risk to public health.
Objective:
6. To protect the public from a serious risk of liver damage from consumption of unlicensed medicines containing Senecio species.
Risk assessment
7. The toxicity of unsaturated PAs, which are found in Senecio species, is well documented. Further information on the toxicity of PAs can be found at Appendix A. Consequently, the use of Senecio jacobaea L. in unlicensed herbal medicines for internal use was restricted to supply in premises which are registered pharmacies, and by or under the supervision of a pharmacist, by the Medicines (Retail Sale or Supply of Herbal Remedies) Order 1977 (SI 1977/2130). The Order, which does not restrict supply of any other Senecio species, reflects the knowledge of use of Senecio at that time and does not necessarily imply that the use of other Senecio species was considered acceptable on public health grounds at the time.
8. Due to the risks associated with this plant genus, the European Union’s Committee on Propriety Medicinal Products (CPMP) included all Senecio species within a list compiled in 1992 of “herbal drugs with serious risks” stating the reason for inclusion as “contains pyrrolizidine alkaloids with genotoxic, carcinogenic and hepatoxic properties”.
9. To date, there have been no formal reports, through the MHRA’s Yellow Card reporting scheme, of adverse reactions in the UK associated with the use of Senecio. This is not necessarily indicative of a lack of risk to public health but may reflect the following factors:
possibly a limited usage of products containing Senecio species by the UK population
consumers may incorrectly assume that herbal medicines are safe and do not cause adverse reactions because they are based on natural ingredients
research shows that patients who consult health professions about a health problem often do not tell the health professional that they have been taking a herbal remedy.
10. Under the current regulatory regime for unlicensed herbal remedies, companies do not notify the MHRA of products they place on the UK market. The number of products in the UK and the level of use by the population are therefore not known. The level of risk to the population can therefore not be determined. All five of the
individuals reporting the supply of Qian Bai Biyan Pian were alerted to the possible inclusion of Senecio within the formulation by the MHRA’s Herbal Safety News WebPages, an Agency publication intended to inform potential users of current safety concerns with herbal remedies. It is possible that other members of the public are not as well informed and that supply is wider than indicated by the reports received to date.
11. The MHRA’s initial assessment is that anyone consuming a product containing Senecio species is at risk of irreversible liver damage resulting in the need for transplantation and/or ultimately death and that there is a need to prevent the supply of all relevant products to the public.
Options
12. Six options have been identified for unlicensed herbal remedies containing Senecio for internal use. In principle, it would be possible to combine several options. The following points require consideration in relation to the options set out below:
all Senecio species contain hepatoxic pyrrolizidine alkaloids. There is no scientific basis for any of the options considered below to be limited to certain species of Senecio or particular parts of plants. Should evidence be forthcoming during consultation which demonstrates certain Senecio species to be safe, the absence of systematic quality controls within some parts of the sector may call into question whether the public could be assured that toxic Senecio species may not be confused with the intended safe species.
on the existing data it is not possible to determine a dosage threshold below which Senecio does not pose a risk to human health and there is therefore no evidence base for any of the options to be restricted to certain preparation strengths or dosages. Unless further evidence is forthcoming which demonstrates the safety of certain posologies, any possible future action will need to be applied equally to all preparation strengths and dosages.
This consultation provides an opportunity to identify any evidence that would allow distinctions to be made and for restrictions to be made in this way. However, even if it is possible to identify certain parameters that would allow certain usage without causing a risk to public health, there would be an issue as to whether quality controls in parts of the sector would be adequate to ensure that remedies met those parameters.
Option 1: Take no further action at this time.
Option 2: Re-establish a voluntary agreement to prevent sale, supply and importation.
Option 3, (a) and (b): Continued availability with warning information about the risks of serious liver damage made available with the product:
- voluntary warnings could be added with the agreement of manufacturers of unlicensed products, or
- warnings could be introduced as a legal requirement.
Option 4: Extend existing statutory restrictions on Senecio species to all Senecio species, restricting supply for internal use through premises which are registered pharmacies and by or under the supervision of a pharmacist.
Option 5: Make all Senecio species Prescription Only Medicines (POMs), limiting supply through a prescription from a doctor or dentist.
Option 6: Prohibit all Senecio species in unlicensed medicines, except those for external use.
Quantifying and valuing the options
Option 1 (take no action)
13. This option would not provide any public health protection. The reports of supply of Qian Bai Biyan Pian indicate possible consumption of Senecio by some members of the public. This is despite two letters from the MHRA to interest groups warning of the dangers of Senecio and stating that Senecio should not be supplied for internal use. If recent reports of supply of Qian Bai Biyan Pian could be regarded as isolated incidents it could be argued that it would be sufficient to take no action other than advising the outlets that had been identified. However, given the evidence of recent supply and the fact that Senecio has recognised uses in some traditional medicines, this option appears clearly insufficient to address the public health risk. Under this option there would be no direct cost to business but any reports of adverse reactions associated with the presence of Senecio in unlicensed medicines could damage sales of herbal medicines and the credibility of the sector.
Option 2 (voluntary agreement to prevent supply)
14. Recent experience of supply of Qian Bai Biyan Pian suggests that the voluntary agreement with trade and practitioner associations may not be fully effective. Moreover, there are many operators who do not belong to an association and are more likely to be unaware of the voluntary agreement and the health risks posed by Senecio species. In order to reach as wide an audience as possible, including those operators who are not members of a Trade Association, the risks associated with Senecio and the action requested by the Agency have been included in the MHRA’s Webpages ‘Herbal Safety News’ on www.mhra.gov.uk However, two of
the reports of supply of Senecio are associated with shops which are members of a Trade Association.
15. There would be no future effective protection if any individual supplier disagreed with the MHRA’s safety assessment.
Option 3, (a) (continued availability with voluntary safety warnings)
16. Warnings could be introduced which explain the risk of serious liver damage posed by Senecio species contained within the products, through a voluntary agreement with the sector. There would be no sanctions or means of enforcement. It is unclear whether there would be full compliance with voluntary arrangements. Regardless of the level of co-operation achieved it is considered that this measure would not introduce the necessary level of public health protection. As there is currently no scientific evidence which supports the safe usage of Senecio, these warnings would only alert consumers to a risk and would not provide any information on how that risk could be avoided.
Option 3, (b) (continued availability with mandatory safety warnings)
17. Products could be required to carry safety warnings, which may include a statement to the effect that Senecio species contained within a product are known to cause serious liver damage, as a legal requirement. This requirement, if breached, would carry sanctions. This could be done by means of regulations made under section 85 of the Medicines Act 1968.
18. The introduction by legislation of label warnings for individual unlicensed remedies would have major drawbacks as a practical way of regulating these products. Overall there are very large numbers of different unlicensed herbal remedies on the UK market, especially when taking into account all the numerous combinations of different ingredients as well as different product strengths and dosage forms. In relation to each of these different products it would be appropriate on public health grounds for manufacturers of remedies to include a range of product specific information about its safe usage, including any appropriate warnings. Although technically feasible, at least in principle, it appears inherently undesirable to the MHRA to go down the route of attempting to set out in legislation what is an appropriate warning information for each remedy.
19. On balance, a voluntary agreement is less likely to capture the co-operation of all suppliers, such as those who are not members of Trade Associations with a robust code of conduct. All suppliers would have to comply with any requirement for mandatory safety warnings, regardless of their links with Trade Associations. However, the MHRA’s assessment is that anyone consuming unlicensed medicines containing Senecio species is at risk of serious liver damage and that there is a need to prevent relevant products being supplied. A warning alone would not help prevent consumers from suffering liver damage and could not be tailored to fit the different species of Senecio or types of products available.
20. In addition there is no evidence of efficacy to balance the extensive evidence that Senecio can cause serious harm. The Agency’s view is that warning information,
whether achieved by compulsory or voluntary means, would therefore be inappropriate and insufficient to address the public health risk.
Options 4 and 5 (make Senecio species Pharmacy Only (P) or a POM)
21. The MHRA considers anyone consuming Senecio species to be at risk regardless of the individual’s medical history, the dosage, strength or type of preparation or length of treatment.
22. Given the toxicity of Senecio, it would not be possible for an unlicensed herbal medicine containing it to be used safely even if used under the supervision of a pharmacist (as a P) or a registered doctor (as a POM).
Option 6 (prohibit all Senecio species in unlicensed medicines for internal use)
23. It is considered that the only realistic route to protect public health is one which will halt the supply of Senecio species in unlicensed herbal remedies. Due to the well documented evidence about the risks posed by Senecio and recent evidence that Senecio may be being supplied in the UK, it was thought necessary to consult upon this option.
Issues of equity or fairness
24. A statutory prohibition would ensure that the same restrictions on sale and supply are applied to all businesses. This would not necessarily be the case with any arrangements which were voluntary.
25. Alternative TCM treatments for the treatment of sinus related problems are quoted within the literature.
26. A notification or ‘draft technical regulation’ (under Directive 98/34/EC) about the proposal has been issued to the European Commission. This will communicate the anticipated effects of the measure and will give other Member States and the Commission an opportunity to raise concerns about potential barriers to trade.
27. The evidence that Senecio is harmful relates only to internal use. In the interests of fairness and proportionality, unlicensed herbal remedies for external use which contain Senecio are not affected by the proposal.
Benefits identified and quantified
28. The proposed legislation will benefit public health by introducing protection against unlicensed herbal remedies containing Senecio. Costs to the National Health Service, for example, due to hospitalisation, and required treatment for liver damage - such as transplantation - could be avoided. It is not possible to quantify the potential benefits since the current use of products containing Senecio is unknown and it is not realistic to try and estimate the possible future use. The Agency is aware of one estimate that the cost of a patient occupying an intensive care bed for 24 hours could be in the order of £1,800.
- Importers supplying herbal material to manufacturers or herbalists.
- Manufacturers and importers of herbal products.
- Wholesalers and retailers of herbal products.
- Herbalists making and preparing herbal medicines to meet an individual patient’s specific needs.
Recurring costs, Non recurring costs and Total Compliance Costs
30. The proposed prohibition itself is likely to have no or little impact on companies adhering to the voluntary withdrawal requested last year. It is likely that companies and practitioners in many parts of the herbal sector do not use and never have used products containing Senecio products as most practitioners accept the evidence that Senecio is toxic.
31. The financial impact for other individual companies will depend upon the amount of herbal remedies containing Senecio which are supplied and how this relates to the overall sales of a business. All the reports to date relate to the supply of one formulation from traditional Chinese medicine (TCM) outlets for the treatment of sinusitis (chronic and acute symptoms of inflamed sinuses). It is likely that a wide range of other products not affected by this proposal are also supplied by these outlets and, on this assumption, it is unlikely that the supply of Qian Bai Biyan Pian would constitute more than a small proportion of total sales for most individual companies. For example, Qian Bai Biyan Pian was only one of 122 different products supplied to consumers by one particular UK based TCM clinic through its internet site.
32. The impact is unlikely to be significant for most businesses, although smaller businesses supplying a limited range of products could be affected more significantly in the short term. In the longer term, any impact could be countered by an adjustment to the products supplied. Stakeholders are asked to comment on the regulatory impact during consultation and this section will be expanded upon once views have been received.
33. In the long term, the level of protection provided by the order may help maintain a growing herbal medicines market.
34. Our understanding from discussions with the Herbal Forum, which represents all the manufacturer’s Trade Associations, including those representing small businesses such as the Association of Small Growers and Suppliers, is that Senecio is not used by the manufacturers and suppliers represented by the Forum and as a result there would be little regulatory impact. It is clear however that Senecio is reaching the market via a variety of other outlets.
35. See paragraph 32 for an initial assessment where other small businesses not represented by the Herbal Forum may supply Senecio containing products.
Competition assessment
36. The favoured option, option 6, is to prohibit use of species of Senecio in unlicensed herbal medicines for internal use. Under this option businesses will be prevented from selling, supplying or importing unlicensed herbal medicine products intended for internal use that contain Senecio. This prohibition would not be expected to affect competition in the unlicensed herbal medicines sector. This conclusion is based on the likelihood that the majority of businesses involved in manufacturing, processing, distribution or sale of herbal medicines in the UK would be unlikely to derive their revenue solely or mainly from products utilising this herb. Whilst this may restrict businesses product range, this restriction will be uniform across the sector.
37. Our initial view is that in most cases unlicensed products containing Senecio would not make up a significant proportion of sales. However, even if previously some business made significant sales of Senecio, many of these businesses have already undertaken a voluntary withdrawal of such products. The prohibition will effectively eliminate the market for unlicensed products for internal use. However, it is not intended that its use will be prohibited in products intended for external use. Moreover, it is likely that substitute products exist for unlicensed Senecio herbal medicine products which would suggest that the relevant market may be wider than that for just these products. Within such a wider market, the significance of any effects may be further reduced. We would welcome comments from stakeholders on this initial view - in particular on the market identified.
Consultation
38. The MHRA wrote to stakeholders in March 2002 to ask for a voluntary withdrawal of Senecio and again in October 2003, after further reports of supply, to remind stakeholders of the position. Stakeholders were asked to let the Agency know if they disagreed with this course of action and nothing was forthcoming. The issue has also been discussed with the Herbal Forum.
39. The proposal to prohibit Senecio species in unlicensed herbal remedies for internal use has been discussed with the Herbal Forum, which represents all UK manufacturer’s Trade Associations. The Better Regulation teams within the
Department of Health and the Cabinet Office; the Small Business Service and the Office of Fair Trading have all been consulted.
Summary and recommendations
Option 1: (take no further action at this time)
40. No public health protection would be provided. Given the toxicity of Senecio this would be inappropriate.
Option 2: (continued voluntary agreement not to supply)
41. A voluntary withdrawal has been in place since March 2002 but given recent evidence of continued supply, this option does not offer sufficient public health protection.
Option 3, a) and b): (continued availability of Senecio with warning information)
42. Warning labels, either on a voluntary or mandatory basis, would represent an insufficient response to the serious risk to public health.
Options 4 & 5: (make Senecio a P or POM)
43. The toxicity of Senecio is such that restricting supply through a pharmacy and under the supervision of a pharmacist or via a prescription from a doctor or dentist would not protect patients.
Option 6: (prohibit Senecio in unlicensed medicines)
44. In view of the nature of the risk, this is the most appropriate option. This is considered necessary in the interests of safety.
Enforcement, sanctions, monitoring and review
45. The prohibition will be enforced by the MHRA’s Enforcement Unit as part of its existing compliance and enforcement responsibilities in protecting public health at no additional cost to the Agency. Offenders will be liable to prosecution and unlicensed herbal medicines for internal which contain Senecio species will be included in the Agency’s regular product monitoring programme.
Contact pointJudith ThompsonMHRA, Market Towers1 Nine Elms lane, London SW8 5NQTel: 020 7084 2945e-mail: [email protected]
APPENDIX A – Toxicity of unsaturated pyrrolizidine alkaloids (PAs)
Background
Pyrrolizidine alkaloidsPyrrolizidine alkaloids are found predominantly in three plant families viz: Asteraceae (Compositae), Fabaceae (Leguminosae) and Boraginaceae. The occurrence, chemistry and toxicity of pyrrolizidine alkaloids is extensively documented in the literature.
Unsaturated pyrrolizidine alkaloids (PAs) are known to be hepatotoxic, carcinogenic and mutagenic. The toxicity of unsaturated PAs is well documented and is based on evidence from cases of human poisoning as well as extensive literature on animal poisoning. The plants may be consumed in some parts of the world as food, for medicinal purposes or as contaminants of other agricultural crops. Cereal crops and forage crops are sometimes contaminated with pyrrolizidine-producing weeds and the alkaloids find their way into flour and other foods, including milk from cows feeding on these plants.
Senecio species Senecio is a plant genus of the family Asteraceae (Compositae). Senecio species contain PAs and the majority reported are the toxic unsaturated compounds such as: senecionine, seneciphylline, retrorsine, jacobine.
A number of Senecio species have been used in herbal medicines throughout the world for a variety of conditions. Senecio species are also ingredients of traditional Chinese medicines (TCM).
The levels of PAs in the Senecio plants is known to vary considerably depending on season, soil type and climate.
Toxicity of the pyrrolizidine alkaloids
A) HUMAN TOXICITY
HepatotoxicityIn almost all cases of human toxicity the patients developed liver damage with cirrhosis and ascites. This type of liver damage is referred to as ‘seneciosis’ or ‘veno-occlusive disease, ‘VOD’’ and is characteristic of PA toxicity.
Most cases of pyrrolizidine alkaloid toxicity result in moderate to severe liver damage. Gastrointestinal symptoms are usually the first sign of intoxication, and consist predominantly of abdominal pain with vomiting and the development of ascites. Death may ensue from 2 weeks to more than 2 years after poisoning, but patients may recover almost completely if the alkaloid intake is discontinued and the liver damage has not been too severe.
Evidence of toxicity may not become apparent until sometime after the alkaloid is ingested. The acute illness has been compared to the Budd-Chiari syndrome (thrombosis of hepatic veins, leading to liver enlargement, portal hypertension, and ascites). Early clinical signs include nausea and acute upper gastric pain, acute abdominal distension with prominent dilated veins on the abdominal wall, fever, and biochemical evidence of liver dysfunction. Fever and jaundice may be present. Chronic illness from ingestion of small amounts of the alkaloids over a long period proceeds through fibrosis of the liver to cirrhosis.
Pulmonary ReactionsIn addition to the liver toxicity, severe pulmonary damage with pulmonary-arterial hypertension and subsequent right ventricular failure have been reported. Lung damage may be prominent and has been fatal.
B) ANIMAL TOXICITY
CarcinogenicityChronic ingestion of unsaturated PAs has led to cancer in animals in experiments, however, to date, no clinical association has yet been found between human cancer and exposure to PAs.
DosageThe daily dose of unsaturated PAs that can give rise to liver disease after chronic ingestion has been estimated to be >1mg/day for 2 weeks or > 0.1mg/day for longer periods. Other studies report the estimated daily intakes of certain PAs leading to fatal intoxications to range from 0.5mg/kg to 3.3mg/kg.
Whilst no epidemiological studies are available which document a possible carcinogenic risk from PAs there are no studies to demonstrate absence of such a risk. In view of the positive animal carcinogenicity studies together with the evidence of genotoxicity it is not possible to establish a safe dose for a potential genotoxic carcinogen without further investigation.
Reports of human poisoning with pyrrolizidine alkaloids
The earliest reports of PA alkaloid poisoning in humans date from the 1920s in South Africa as a result of ingestion of Senecio species. Since then numerous cases of mass human poisonings have been reported notably when cereal crops have been contaminated with seeds containing PAs.
Cases of severe liver damage have also been found with PA-containing plants used for medicinal purposes including cases in Central America and Jamaica. The use of medicinal ‘bush-teas’ prepared from Senecio and Crotalaria species in Jamaica is thought to be linked with the many cases of liver damage reported in children.
Twenty specific cases of human toxicity have been reported in the literature as due to a number of PA containing plants; of these, six cases have resulted from ingestion of Senecio species.
Senecio species In the U.S (1977), a two-month-old infant in Arizona experienced veno-occlusive liver disease after being treated with gordolobo yerba, one of the most popular of Mexican herbs, usually obtained from Gnaphalium, but sometimes substituted by the similarly appearing Senecio longilobus. The case, involved portal hypertension and extensive hepatic fibrosis: the child subsequently died of the disease.
An additional case (1978) of an infant administered Senecio longilobus as gordolobo yerba, used to make herbal cough medicine, involved a 6-month-old female. She had acute hepatocellular disease, ascites, portal hypertension, and a right pleural effusion. She improved with treatment. However, after 6 months, a liver biopsy revealed extensive hepatic fibrosis, progressing to cirrhosis over 6 months.
Hepatomegaly and sudden adcites developed in a Portugese father and his son following the use of a herbal tea prepared from an unspecified Senecio plant (1987).
An elderly patient taking a tea of Senecio vulgaris continuously for two years suffered from veno-occlusive liver disease (1995).
A woman taking Senecio tephrosioides as a cough remedy on an occasional basis but for many years was diagnosed with hepatic veno-occlusive disease (1995).
The Medicines for Human Use (Senecio)(Prohibition) Order 2004
Made - - - - 2004
Laid before Parliament 2004
Coming into force - - 2004
As respects England, Wales and Scotland, the Secretary of State concerned with health in England and as respects Northern Ireland, the Department of Health, Social Services and Public Safety, acting jointly, in exercise of the powers conferred upon them by section 62(1)(a) and (2) of the Medicines Act 1968(1) or, as the case may be, the powers conferred by those provisions and now vested in them(2), and of all other powers enabling them in that behalf, it appearing to them to be necessary in the interests of safety to make the following Order, after consulting such organisations as appear to them to be representative of interests likely to be substantially affected by the Order pursuant to section 129(6) of that Act, after consulting and taking into account the advice of the Committee on Safety of Medicines pursuant to sections 62(3) and 129(7) of that Act(3), [and after taking into account the report of the Medicines Commission made under section 62(5) of that Act], hereby make the following Order:
Citation, commencement and interpretation
1.— This Order may be cited as the Medicines for Human Use (Senecio) (Prohibition) Order 2004 and shall come into force on 2004.
(1) In this Order—“the Act” means the Medicines Act 1968;
1 (?) 1968 c.67; the expression “the appropriate Ministers” and the expression “the Health Ministers”, which are relevant to the powers being exercised in the making of this Order, are defined in section 1 of that Act, as amended by article 2(2) of, and Schedule 1 to, S.I. 1969/388 and by article 5 of, and paragraph 1(1) of the Schedule to, S.I. 1999/3142.
2 (?) In the case of the Secretary of State concerned with health in England, by virtue of article 2(2) of, and Schedule 1 to, S.I. 1969/388, and articles 2(1) and 5 of, and paragraph 1(1) of the Schedule to, S.I. 1999/3142; and in the case of the Department of Health, Social Services and Public Safety, by virtue of the powers vested in the Minister in charge of that Department by virtue of section 95(5) of, and paragraph 10 of Schedule 12 to the Northern Ireland Act 1998 (c.47) which may now be exercised by the Department by virtue of section 1(8) of, and paragraph 4(1)(b) of the Schedule to, the Northern Ireland Act 2000 (c.1); the Department was renamed by virtue of Article 3(6) of S.I. 1999/283 (N.I.1).
3 (?) Section 62(3) refers to the “appropriate committee”, which is defined in section 4(6) of the Act. The Committee on Safety of Medicines was established under section 4 of the Act, by S.I. 1970/1257, for the purposes set out in that instrument.
“EEA Agreement” means the Agreement on the European Economic Area signed at Oporto on 2nd May 1992(4) as adjusted by the Protocol signed at Brussels on 17th March 1993(5);“EEA State” means a State which is a Contracting Party to the EEA Agreement;“external use” means application to the skin, hair, teeth, mucosa of the mouth, throat, nose, ear, eye, vagina or anal canal when a local action only is intended and extensive systemic absorption is unlikely to occur, and references to medicinal products being “for external use” shall be read accordingly – except that such references shall not include throat sprays, throat pastilles, throat lozenges, throat tablets, nasal drops, nasal sprays, nasal inhalations or teething preparations;“free circulation in member States” has the same meaning as in Article 23.2, as read with Article 24, of the Treaty establishing the European Community; and “medicinal product” does not include a medicinal product which is a veterinary drug.
Prohibition of sale, supply and importation of any medicinal product consisting of or containing Senecio
2. Subject to article 3 below, the sale, supply or importation of any medicinal product consisting of or containing—(a) a plant(6) belonging to the species Senecio; or(b) an extract from such a plant, is prohibited.
Exceptions to the prohibition imposed by article 2
3. The prohibition imposed by article 2 above shall not apply where the medicinal product is—(a) for external use only;
(b) sold or supplied to, or is imported by or on behalf of, any of the following persons—(i) an authorised officer within the meaning of section 5(6) of the Food Safety Act
1990(7) or Article 2(2) of the Food Safety (Northern Ireland) Order 1991(8),(ii) a food analyst or food examiner within the meaning of section 30 of the Food Safety
Act 1990(9) or Article 30 or 31 of the Food Safety (Northern Ireland) Order 1991(10),(iii) a person duly authorised by an enforcement authority under sections 111 and 112 of
the Act, or(iv) a sampling officer within the meaning of Schedule 3 to the Act(11);
(c) imported from an EEA State, if the product—(i) originates in an EEA State, or
(ii) originates outside the European Economic Area, but is in free circulation in member States,
and is being, or is to be, exported to an EEA State other than the United Kingdom; or(d) the subject of—
(i) a product licence(12),
4 (?) OJ No. L1, 3.1.1994, p.3. 5 (?) OJ No. L1, 3.1.1994, p.572.6 (?) “Plant” includes part of a plant; see the definition of “plant” in section 132(1) of the Act. 7 (?) 1990 c.16; section 5(6) was amended by paragraphs 7 and 8 of Schedule 5 to the Food Standards Act 1999 (c.28).8 (?) S.I. 1991/672 (N.I. 7); article 2(2) was amended by articles 3(1) and 7(1) of the Food Safety (Amendment) (Northern
Ireland) Order 1996 (S.I. 1996/1633 (N.I.12)) and paragraphs 26 and 29 of Schedule 5 to, and Schedule 6 to, the Food Standards Act 1999.
9 (?) Section 30 was amended by paragraphs 7 and 8 of Schedule 5 to the Food Standards Act 1999.10 (?) Article 31 was amended by paragraphs 26 and 35 of Schedule 5 to the Food Standards Act 1999.11 (?) Schedule 3 was amended by paragraph 12 of Schedule 3 to the Food Safety Act 1990.12 (?) “Product licence” has the meaning assigned to it by section 7 of the Act.
(ii) a marketing authorization within the meaning given in regulation 1(4)(a) of the Medicines for Human Use (Marketing Authorisation Etc) Regulations 1994(13), or
(iii) a certificate of registration within the meaning given in regulation 1(2) of the Medicines (Homoeopathic Medicinal Products for Human Use) Regulations 1994(14).
Signed by authority of the Secretary of State for Health
Parliamentary Under Secretary of State 2004 Department of Health
Sealed with the Official Seal of the Department of Health, Social Services and Public Safety
Permanent Secretary 2004 Department of Health, Social Services and Public Safety
13 (?) S.I. 1994/3144; as amended by S.I. 1998/3105, 2000/292, 2001/795, 2002/236 and 542, and 2003/1618 and 2321.
14 (?) S.I. 1994/105; as amended by S.I. 1995/541, 1996/482, 1998/574, 1999/566, 2000/592, 2001/795, 2002/236 and 542, and 2003/625 and 2321.
This Order prohibits the sale, supply or importation of any medicinal product for human use which consists of or contains a plant (or part of a plant) belonging to the species Senecio or an extract from such a plant.
This prohibition is subject to the following exceptions—(a) where the product is for external use only;(b) where the sale or supply is to, or the importation is made by or on behalf of, a person
exercising functions in relation to the enforcement of food or medicines legislation;(c) where the product is imported from an EEA State, if it originates from such a State or
originates outside the EEA but is in free circulation in Member States (within the meaning of Article 23.2, when read with Article 24, of the EC Treaty), and is being, or is to be, exported to an EEA State other than the United Kingdom;
(d) where the product is the subject of a product licence, marketing authorization or homoeopathic certificate of registration.
This Order was notified to the European Commission in accordance with Article 8 of the European Parliament and Council Directive 98/34/EC (OJ No. L204, 21.7.1998, p.37), as amended by Article 1(4) of the European Parliament and Council Directive 98/48/EC (OJ No. L217, 5.8.1998, p.18).
A Regulatory Impact Assessment in relation to this Order has been placed in the libraries of both House of Parliament, and copies can be obtained from the Medicines and Healthcare products Regulatory Agency, Information Centre, Room 10-202, Market Towers, 1 Nine Elms Lane, London, SW8 5NQ.
Miss Alexandra WilliamsonMedicines and Healthcare Products Regulatory AgencyRoom 16/131 Market Towers1 Nine Elms LaneLONDON SW8 5 NQ
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