Letter from Anne Milton, Minister for Public Health to Eric Ollerenshaw (09 March 2011)

Eric Ollerenshaw OBE MP
House of Commons

09 March 2011

Thank you for your letter of 4 February about issues related to those discussed atthe meeting on 8 December 2010 with you and Jim Dobbin.

As requested, I have looked into and will address each of your questions in turn.

1. The Summary of Product Characteristics (SPC) is a document that reflects what is known about the medicine to support its safe use. The SPC is the definitive description of the product both in terms of its properties, chemical, pharmacological and pharmaceutical, and the clinical uses to which it can be put. The SPC outlines the terms of the licence for healthcare professionals providing information to ensure the medicine is used as safely and effectively as possible and can only be amended with approval from the Medicines and Healthcare products Regulatory Agency (MHRA).

However, the SPC does not contain all of the original documents, but it does reflect the data provided in the original application as well as the safety data gathered throughout its time on the market. Relevant data are summarised in the ten pages or so of an SPC. For example, a short paragraph on the approved indications is based on a review of all of the clinical trials available.

2. Some SPCs are available on the electronic Medicines Compendium website, www.medicines.org.uk. However, this web site is not authorised by the MHRA. It is independent and companies pay a fee to include their product information on this site. In the past, there have been generic lorazepam SPCs on this site but this is no longer the case.

There is currently not a single specific site that contains all of the lorazepam SPCs. Many pharmaceutical companies provide their SPCs on their websites but these may only be accessible to health professionals.

On 22 December I provided Mr Behan and Jim Dobbin with copies of several SPCs for generic lorazepam products and I am enclosing copies of these. Iwould like to reassure you that prescribers are able to access information about the medicines they prescribe from multiple sources. All prescribers in the NHS have access to the British National Formulary, which includes prescribing guidance based on the approved SPCs.

3. I can confirm that the response by the then Health Minister, Dawn Primarolo, in reply to a question by Jim Dobbin [Hansard 196407] was correct. I can also confirm that, since the reply, there have been investigations into companies suspected of withholding safety information but these have not resulted in prosecutions.

The MHRA is responsible for the regulation and control of medicines for human use on the UK market. Additionally, the MHRA has responsibility, on behalf ofthe Secretary of State for Health, to enforce the provisions of the 1968 Medicines Act and regulations made under it. The MHRA investigates all suspected breaches of medicines legislation and takes appropriate action. Prosecutions are routinely brought against those found in breach of the requirements of medicines regulations.

4. With regard to your recent Parliamentary Questions, the MHRA has confirmed that a total of 28 generic licences have been issued for lorazepam. The list provided for the Parliamentary Question [Hansard 31749] is correct. However, the status of licences can change at any time and some are sold to other pharmaceutical companies through a Change of Ownership Application (COA).

The licences for Genus Pharmaceuticals and Chelonia Healthcare Ltd were the subject of such COAs. Two of the original licences held by John Wyeth &Brothers Ltd (pL 00011/0108 and PL 00011/0109) were transferred to Genus Pharmaceuticals in 1999 and became PL 17225/0010 and PL 17225/0011. The other COA involved PL 00225/0063 and PL 00225/0075 held by DDSA Pharmaceuticals Ltd. These were transferred to Chelonia Healthcare Ltd in 2009 and became PL 33414/0056 and PL 33414/0057. These COAs do not change the total number of generic licences issued. There has not been any other COA for lorazepam products.

5. The term ‘not confirmed’ provided in the response to your Parliamentary Question [Hansard 31749] was used for those applications made under Article 4.8a (of Directive 65/65/EEC) when the precise legal basis (under section (i), (ii)or (iii)) could not be confirmed.

The MHRA currently holds data on medicinal products on an electronic database. Historically, the legal basis of an application has not been recorded in a searchable form and so information for the lorazepam applications was established by manually reviewing available records.

Where the precise legal basis has not been confirmed from the manual search such as when the original applications have been destroyed it is shown as ‘not confirmed’. However, all the applications would have been made under Article 4.8a of Directive 65/65/EEC.

6. At the time these lorazepam Marketing Authorisations were submitted, the active directive on medicinal products was Directive 65/65/EC. Applications for generic products would have been made under Article 4.8a, which made provision for an abridged application, that is, an application made without supplying results of toxicological tests and clinical trials.

The current legislation, which allows for the submission of applications without supplying results of toxicological tests and clinical trials, is Directive 2001/83/EC. In answer to your Parliamentary Question [Hansard 21751], it was explained that under the current Directive 2001/83/EC, clinical trial data are not required for generic licence. In answer to your Parliamentary Question [Hansard 31749], Directive 65/65/EC was referred to because this was the relevant Directive in force prior to it being superseded by Directive 2001/83/EC. Depending on when applications were made, they would have been made undereither one or the other.

An abridged application under Directive 65/65/EC was permitted if:
(i) the holder of an existing authorisation gave consent for their clinical and toxicological data to be cross-referenced;
(ii) the product had well established use with recognised efficacy and an acceptable level of safety; or
(iii) the medicinal product was essentially similar to a product that had been authorised on the basis of full data on safety and efficacy including clinical trials.

No further details of the legislative basis beyond those previously provided [Hansard 31749] are available. However, Article 4.8a (iii) was generally the most commonly used basis for abridged applications at that time.

7. When benzodiazepines were introduced into the market in the UK there was not a formal system of medicines regulation. In 1971, a formal system was introduced, following the implementation of the Medicines Act 1968. All medicines were given a Licence of Right, and these licences were reviewed overtime by the Committee on Review of Medicines (CRM) and granted a Reviewed Licence if they met the requirements of safety, efficacy and quality.

Ativan received a Licence of Right that was subsequently reviewed by the CRM and considered to have sufficient evidence of safety, efficacy and quality.

As previously indicated, the MHRA no longer holds the original licence application documents for longer than 15 years and therefore cannot provide the original safety evidence for Ativan and the lorazepam licences. However, the CRM assessments from this period can be accessed at The National Archive(TNA).

8. I am aware of Professor Lader’s research from 1981, which was brought to the attention of the Department of Health and the MHRA last year. No regulatory action was taken in 1981 as I understand that the MHRA was only recently informed of the research.

9. In the answer to the Parliamentary Question to which you refer, it was reported that clinical trial files are held for five years only. This is correct. I understand from the MHRA that clinical trial files relate to applications to run clinical trials prior to application for a product licence and do not contain clinical trial data that support an application for a product. Not all applications to run clinical trials result in an application for a product licence.

10. The MHRA reviewed its records management policy during 2009/10 resulting in a revised policy that was developed in the light of how products are monitored and updated once they are on the market. The revision of the policy also came about because of a decision by the Information Commissioner in 2009 that the MHRA’s legacy records were not properly organised. The MHRA’s new records management policy has the approval of TNA.

The MHRA’s policy is that data are only retained for 15 years, regardless of whether or not the products are still on the market. For all other documentation relating to all work across the Agency, the dates for retention range from one year to 15 years, depending on the nature of the records and the business need.

There are exceptions to the rules and these include all committee papers, which are retained by the MHRA for 25 years, and these are all transferred to TNA after 30 years. There are other exceptions for retaining records longer and decisions on these are made on a case by case basis. These may include specific drug safety data and other issues of importance that will be retained for longer specified periods and reviewed with a view to whether or not they should be retained for the public interest, and thus eventually referred to TNA.

I am satisfied that the Agency has had much more robust arrangements in place for managing paper archived material for a number of years now, including the recording of destruction dates, so this is not a continuing problem.

11. The reports commissioned to gather evidence on addiction to medicines will be published over the next couple of months. Following publication, we will be engaging widely with interested parties to determine the future direction of policy and service planning.

Please do contact me again if there are any further concerns.

Anne Milton

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