Department of Health
Market Towers 1 Nine Elms Lane London SW8 5NQ
Telephone 0171-273 0600
Facsimile 0171- 273 0737 .
our ref : OG 99/46
24 January 2000

Dear Mr Medawar,

Thank you for your letter of 26 October 1999 concerning the product Detrusitol. I repeat Mrs Thyer's earlier apologies that this reply has been delayed. Detrusitol was first licensed in Sweden under the Mutual Recognition procedure. Sweden was the Reference Member and all 14 of the other Member States were also involved in the procedure. Chapter 2 ("Mutual Recognition") of Volume 2A of the "Notice to applicants for marketing authorisations for medicinal products for human use in the European Union" provides the detail of the MR procedure and that document is available from the EMEA.

Section 1 of the Chapter concerns the legal basis and purpose of the procedure and states that "...a Marketing Authorisation in one Member State ought in principle to be recognised by the competent authorities of the other Member States (unless there are serious grounds for supposing that the authorisation of the medicinal product concerned may present a risk to human health)". Section 4.5 states that "The (Marketing Authorisation Holder) is required to give an assurance that:

(a) the data submitted by the company (the dossier) is identical, including any approved variations, to that accepted by the Reference Member State, or to identify any additions,

(b) the Summary of Product Characteristics (SPC) is identical, and

(c) the dossier and SPC as submitted are identical in all concerned Member States.

As is the case for all new-drug applications in the UIK, the dossier was assessed by the MCA and the assessment report and the SPC were considered by the Committee on Safety of Medicines (CSM). For mutual recognition applications the assessment report prepared by the Reference Member State is also considered by the CSM. The SPC for Detrusitol that has been approved in the UK is identical to that approved in all other Member States.

Turning now to your specific questions and requests:

Please supply a copy of the full terms of the licence [for Detrusitol], together with the minute(s) of any CSM or sub committee discussion about [its] safety/efficacy within the last five years

I enclose a copy of the licences for the 1mg and 2mg dosages of Detrusitol. Those documents have been edited in accordance with exemption 13 (third party commercial confidences) of the Code of Practice on Access to Official Information (the Code). I also enclose a copy of the minutes of the CSM meeting of 12 November 1997 and the Sub Committee on Chemistry, Pharmacy and Standards (CPS) which met on 6 November 1997. As you will see, Detrusitol is item 5.3 in the CPS minutes and the attachment B3 records the CPS decision. Detrusitol is at item 6.3 of the CSM minutes of 12 November 1997 and the attachment provides the CSM's advice. Again the documents have been edited under exemption 13 of the Code.

Is the MCA satisfied with the advertisement [in the BMJI? If not what steps will be taken?

The MCA has considered the advertisement for Detrusitol published in the BMJ, together with other advertisements, as part of our post marketing surveillance for this newly marketed medicine. The advertisement was considered to be potentially misleading in respect to certain claims made for the product [by exaggerating the properties of the product] and therefore potentially in breach of regulation 3A(2) of the Medicines (Advertising) Regulations 1994. The company was informed of the MCA's decision and agreed to amend future advertising. The advertisement was not considered to be misleading as to safety, quality or efficacy.

You may be interested to know that Section 96 of the Medicines Act 1968 no longer applies to relevant medicinal products (as defined in the Regulations) by virtue of paragraph 7 to that section inserted by regulation 2 of the Medicines Act Amendment Regulations 1995 (SI No. 2321). Similarly, wherever possible, the question of whether an advertisement could be misleading is determined by reference to the provisions of regulation 3A of the Advertising Regulations, inserted by regulation 3 of the Medicines (Advertising and Monitoring of Advertising) Amendment Regulations 1999 (SI No. 267). The Amending Regulations have the effect of completing the implementation of Directive 92/28/EC into UK law thereby avoiding the need to refer back to the Medicines Act for certain provisions.

What justification can there be for the lack of guidance in the data sheet about the recommended duration of treatment - apart from the statement that "after 6 months suggests [a] that reliable efficacy data is available only for 4-week and 12-week weeks)?

The company submitted data on an open long-term assessment of efficacy and safety. The duration of the study was 6 months. The data indicated that the therapeutic benefit of Detrusitol was maintained with no increase in the frequency or severity of adverse events over time. A review of all the evidence indicated that when compared with placebo treatment, Detrusitol at the recommended dose decreased the average number of incontinence episodes and the number of micturitions over 24 hours, and increased the mean volume voided per micturition. The risk/benefit analysis was therefore positive for Detrusitol.

On the advice of the CSM the UK considered that there were grounds for supposing that the authorisation of Detrusitol might present a potential public health issue unless amendments were made to the SPC. One amendment was that the indication should be limited to idiopathic detrusor instability. The other amendment was that myasthenia gravis should be included as a contraindication. After considering the views of the company, the Reference Member State (Sweden) and those of other concerned Member States, the UK accepted the indication as outlined in the SPC authorised by Sweden. The contraindication in patients with myasthenia gravis was agreed by all Member States.

It seems to me very unusual to find such bald evidence of limited efficacy in a Data Sheet/SPC, and it seems safe to assume that the Table was inserted at the insistence of the licensing authorities and against the wishes of the Licence holder. Can you please confirm this, indicating also whether this signals some general change of policy by the MCA/CSM - i.e. that more data on lack of efficacy should be included in Data Sheets/SPCs?

The original SPC was authorised by the Swedish regulatory authority. It is not unusual for SPCs authorised by Sweden to include some details of the efficacy data in 5.1 of the SPC although the CPMP SPC guideline does not require any such data to be included. I enclose as Annex 1 a table which compares the current guidance on Section 5.1 (left column) with the revised guidance (which has not yet been adopted). In neither the current nor the proposed revision is it expected that clinical efficacy data for drugs such as Detrusitol should be included. That said, although the UK objected to some aspects of the efficacy data table approved by the Swedish authorities, the inclusion of these data was not regarded as a potential risk to human health. Accordingly, the issue was not pursued to the point of arbitration.

If you consider that any information has been unreasonably withheld under the Code you may, as you know, ask for an internal review of my decision. If you wish to do so, please contact me in the first instance. If you remain dissatisfied, you can ask a Member of Parliament to make a complaint on your behalf to the Parliamentary Commissioner for Administration who may decide to conduct his own investigation.

Yours sincerely
R.K. Alder
Head of Executive Support


Contents page
List of correspondence with MCA/CSM