Department of Health
MEDICINES CONTROL AGENCY
Market Towers 1 Nine Elms Lane London SW8 5NQ
Telephone 0171-273 0600
Facsimile 0171- 273 0737 .
31 March 2000

Dear Mr Medawar,

Dr Jones' recent letter confirmed that he had made arrangements for an internal review of the reply sent by Anne Thyer on 3 February following your request for information about dosage formulations for fluoxetine.

That internal review has now been completed and I enclose a copy of Dr Pugh's report. As you will see, Dr Pugh has recommended that the MCA, as part of the process for the renewal of the product licence, should approach the licence holder about lower strength formulations. The licence for Prozac is, I understand, due for renewal in December and I will arrange for Dr Pugh's recommendation to be taken forward as part of that process.

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
Roy Alder
Head of Executive Support

OG 99150: REQUEST FROM MR CHARLES MEDAWAR FOR AN INTERNAL REVIEW OF THE HANDLING OF HIS REQUEST FOR INFORMATION ABOUT THE AVAILABILITY OF LOW DOSE FLUOXETINE 

1. Introduction

Mr Medawar wrote to the Agency on 1 December 1999 regarding fluoxetine and the recent acceptance by the FDA of low dose tablets (5 & 10mg) of a product that is only currently available in the UK as 20mg strength dose products (capsule & syrup). A response was sent to Mr Medawar on 3 February 2000 and he wrote again to Dr Jones on 12 February expressing his dissatisfaction at the content of the response. In the letter he requested that the Agency either revisit his original request or formally review its response in accordance with its procedures. A decision has been made to do the latter.

2. Circumstances leading to the complaint

NU Medawar's letter dated 1 December which was accompanied by a paper he had also written, concerned Prozac. The paper related to the safety of Prozac and expressed concern about the lack of warnings regarding akathisia. The questions in the letter are summarised below: -

1. Is the MCA/CSM aware of why the FDA approved the introduction of the 10mg and 5mg strengths of Prozac tablets?

2. If so, will the MCA/CSM explain why the benefits of those low dose options should not be available in the UK

3 . If the MCA/CSM is not aware of the reasons behind the FDA's decision, will the MCA seek to find out [and let him know]?

4. Will the MCA/CSM formally ask the MA holder why they do not intend to introduce the low dose forms in the UK [and as a follow through disclose our enquiry and encourage the company to disclose their reply]?

5. How can it be justified to continue Prozac in a single dose solid form?

Mr Medawar was not happy with the response he received dated 3 February and

he formally requested a review of the handling of his original request in a letter dated 12 February to which he again attached a copy of his report.

The main criticisms highlighted in the letter were: -

The Agency had been unreasonable not to respond properly in the light of the safety issues.

The response fell short of the required standards and it was not positive.

Content and tone of the letter was influenced by the Agency's attitude to the sender.

The quoting of the exemption clause regarding the access to information had been miss-applied because the original question had been wrongly interpreted.

The Agency had not provided adequate reasons for not contacting the MA holder.

Straight answers had not been given to straight questions.

3. Regulatory status of Prozac

Prozac is currently available in the UK as 20 & 60mg capsules and a 20mg/5ml syrup. It is indicated primarily for depression and also Obsessive-compulsive disorder, Bulimia nervosa, Pre-menstrual Dysphoric Disorder (PIMD), Diagnosis of PNMD. A starting dose of 20mg is normally recommended for all the indications but higher doses can be given. Use in children is not recommended.

Several Marketing Authorisations for the generic version of fluoxetine capsules are available in the UK. Marketing Authorisation applications through the mutual recognition procedure for a generic version of 20mg strength capsules were the subject of a CPW arbitration procedure in December 1997.

4. Review Process

I have conducted the review using the appropriate Standard Operating Procedure (SOP G3.97), the Open Government Code of Practice on Access to Government Information, Second Edition (1997) and the Department of Health Internal Review Guidelines.

Process followed in Assessing Mr Medawar's Appeal Against the Content of the Agency's response to his letter concerning Prozac dated 1 December 1999:

- A review of the relevant Code of Practice on Access to Government Information documents and the guidance on interpretation.

- A review of the various items of correspondence provided to me with the request to assess the appeal.

- A review of the PLUS computer system to clarify the current licensing status of fluoxetine formulations.

- Consultation with Dr C Parikh (Medical Assessor) to obtain clinical advice regarding the comments made in Mr Medawar's letters and to the general safety of fluoxetine.

- Consultation with Miss S Norton, Group Manager, Post Licensing Assessment Group

5. MCA response to Mr Medawar dated 3 February 2000

Having reviewed all the information I concluded that the original query had been considered widely by appropriate personnel across the Agency. I decided that for clarity the best approach was to provide comments against the summary of questions presented (circumstances leading to the complaint) and the responses are as follows:-

Is the MCA/CSM aware of why the FDA approved the introduction of the 1Omg and 5mg strengths of Prozac tablets?

Response - reference is made to the Code of Practice (departments are not required to obtain information that they do not possess) and refers Mr Medawar to the FDA.

Comment - the basis for the FDA's decision would require the Agency to seek information from the FDA. Since the information is not directly available to the Agency and the Code does not require that the information be sought, this is considered to be an acceptable response.

2. If so, will the MCAICSM explain why the benefits of those low dose options should not be available in the UK?

Response - no specific comment

Comment - This question is linked directly to point 1. In the absence of the information the Agency was not in a position to specifically comment. It is considered that the absence of a specific comment does not compromise the Code as for point 1.

It is considered that a general comment could have been included in the response which confirms that the MCA would consider any application made for low dose options together with appropriate justification that no safety, quality and, specifically in this instance, efficacy concerns arise. However, in any event, details of any pending applications could not be disclosed in accordance with a policy that the Parliamentary Ombudsman has upheld.

3. If the MCAICSM is not aware of the reasons behind the FDA's decision, will the MCA seek to find out [and let him know]?

Response - no specific comment

Comment - It is considered that the absence of a specific comment does not compromise the Code because there is no obligation to get the information. However, it would have been helpful if an explanatory sentence had been included illustrating the possible different prescribing practice in the US including extensive use of the drug in children (a use which is not recommended in the UK).

4. Will the MCA/CSM formally ask the AM holder why they do not intend to introduce the low dose forms in the UK [and as a follow through disclose our enquiry and encourage the company to disclose their reply]?

Response - company will not be contacted

Comment - the response indicated that in the light of the currently available information, there was no need to formally contact the company. This is considered to have been a reasonable judgement in the circumstances bearing in mind that companies are responsible for developing their products and they are normally proactive in this. However, bearing in mind the likely significance of the developments in the US, it is considered that the MA holder should be contacted as part of the renewal procedure. They should be asked to establish what the rationale/needs were for the low dose products in the US and to clarify its possible strategy for any related European submissions.

5. How can it be justified to continue Prozac in a single dose solid form?

Response - no specific comment

Comment - the point should have been made that a syrup presentation is also available in the LTK, which could be used to provide lower doses than 20mg by possible dilution. However, the licensed posology for each indication is currently based upon a minimum dose of 20mg and the available dosage forms and the strengths fit in with this. This has been based upon clinical trials submitted in support of the original Marketing Authorisation Applications and the recommended posology reflects the current optimum risk:benefit balance of the drug. It is considered that the absence of a response does not compromise the Code because the information is already readily available in the public domain to the requester.

Other comments on the response: -

The comment regarding safety and posology is considered to be accurate for the drug. However, a general comment acknowledging the possibility for the reduced incidence and seriousness of side effects with lower doses could have been included and the development of such products encouraged if there was a clinical need.

The statement regarding the CPW arbitration (12/97) could have been more clearly stated e.g. "The Agency is aware that the CPNT arbitrated on a fluoxetine capsule application during 1997 and this resulted in an agreed European SMPC for fluoxetine 20mg".

It is considered that a comment could have been included in the response specifically regarding akathisia which, is highlighted in the submitted paper e.g. "Movement disorders are described as adverse effects in the SmPCs and product literature, although akathisia is not specifically mentioned. Akathisia is more widely associated with anti-psychotic drugs; however the Agency will keep this issue under review.

6. CONCLUSION

Having considered all the facts and available information I conclude that the Agency's response to Mr Medawar was fair and did not compromise the Code.

I have not found any evidence from the internal correspondence that Mr Medawar's letter was treated any differently to that from any other person and that consequently the contents of a response would have been the same.

Available information was provided as part of the response and where it was not or no comment made this was done correctly in accordance with the Code. The non release of information was either made on the basis that the Agency did not have the necessary information or that in one instance the information on pending applications could not be released in accordance with a policy that the Parliamentary Ombudsman has upheld.

However, even though the information in the response is factually correct I consider that a more complete, helpful and positive response could have been provided if the following comments, that I have already highlighted, had also been included in the response: -

It is acknowledged that the currently available capsule formulations do not allow for dose flexibility. However, the licensed posology for each indication is currently based upon a minimum dose of 20mg and the available dosage forms and strengths fit in with this. This has been based upon clinical trials submitted in support of the original Marketing Authorisation Applications and the recommended posology reflects the current optimum risk:benefit balance of the drug. In patients with renal and/or hepatic dysfunction, a lower dose e.g. alternate day dosing, is recommended. It should be noted that Prozac is also available as a syrup (20mg/5ml). This has the same posology and indications as the capsules but this presentation should allow lower doses of Prozac to be given if necessary.

It is recognised that the availability of lower dose products should reduce the incidence and seriousness of any side effects and consequently would be welcomed. However, the lower dose products would need to be shown to be efficacious at the recommended dosage. It is noted that prescribing practice can differ significantly between countries, and this can include off-label use, such as the use of the drug in children.

Movement disorders are described as adverse effects in the SmPCs and product literature, although akathisia is not specifically mentioned. Akathisia is more widely associated with anti-psychotic drugs; however the Agency will keep this issue under review.

I recommend that these additional comments, which aid clarity, are made available to Mr Medawar as part of a response to his letter dated 12 February. In addition, in view of the potential significance of the developments in the US I recommend that the MA holder in the UK be approached to clarify its position on any possible European strategy with regards to the lower strength products. This could be done in a reasonable timeframe as part of the Renewal process (when the first of the products within the Prozac range next becomes due for renewal). Mr Medawar should be advised of this.

Dr K Pugh
Variations Team Leader
16 March 2000
Contents page
List of correspondence with MCA/CSM