1 Nine Elms Lane

Market Towers

1 Nine Elms Lane

London SW8 5NQ

Tel:020 7084 2068

Fax:020 7084 2387

E mail:

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.

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

Should you have any questions regarding the proposals or the conduct of the consultation exercise, please contact Judith Thompson (Tel: 020 7084 2945, Email: ).

Replies should arrive at the MCA no later than. Friday 23rd April 2004. Please send your replies using the attached form to:

Alexandra Williamson

16 – 131 Market Towers

1 Nine Elms Lane

London SW8 5NQ

Tel:020 7084 2970

Fax: 020 7084 2387

e-mail:

Yours faithfully

Richard Woodfield

Group Manager Herbal Policy

Consultation MLX 296: Proposals to prohibit the sale,

supply or importation of unlicensed herbal medicinal

products for internal use which contain Senecio species

PROPOSALS TO PROHIBIT THE SALE, SUPPLY OR IMPORTATION OF UNLICENSED HERBAL MEDICINAL PRODUCTS FOR INTERNAL USE WHICH CONTAIN SENECIO SPECIES

Summary......

Background......

Senecio

Regulation of medicines containing Senecio species in the United Kingdom......

The risk to consumer health......

Recent Action in the UK......

The proposal......

Herbal medicines affected by the proposal......

Other exceptions......

Other options considered......

Timetable......

Publication of comments......

DRAFT PARTIAL REGULATORY IMPACT ASSESSMENT

Purpose and intended effect of the proposal

Issue:......

Objective:......

Risk assessment

Options

Quantifying and valuing the options......

Issues of equity or fairness

Benefits identified and quantified

Compliance costs for business......

Business sector affected......

Recurring costs, Non recurring costs and Total Compliance Costs......

Small firms impact test......

Competition assessment

Consultation

Summary and recommendations

Enforcement, sanctions, monitoring and review

APPENDIX A – Toxicity of unsaturated pyrrolizidine alkaloids (PAs)...... 17

ANNEX B – draft Statutory Instrument...... 20

ANNEX C – Reply form...... 24

ANNEX 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

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 Senecioscandens,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.

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.

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).

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 theMHRA using the enclosed reply form at Annex Cby 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

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 speciesin the United Kingdom

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.

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

Prior to March 2002, the Agency was not aware of the supply of unlicensed herbal remedies containing Senecio species.

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 Senecioscandens,had been placed on the UK market.

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.

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.

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.

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”.

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

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

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.

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.

Herbal medicines affected by the proposal

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.

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.

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.

This proposal does notaffect 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

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

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

The consultation period will close on Friday 23 April 2004.

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

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.

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.

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.

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: ).

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.

ANNEX A

DRAFT PARTIAL REGULATORY IMPACT ASSESSMENT (RIA)

– 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:

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.

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.

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.

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.

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:

To protect the public from a serious risk of liver damage from consumption of unlicensed medicines containing Senecio species.

Risk assessment

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.

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”.

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.

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.

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

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.