MHRA

The Medicines and Healthcare products Regulatory Agency (MHRA) was set up in April 2003 from a merger of the Medicines Control Agency and the Medical Devices Agency. The MHRA is the government agency which is responsible for ensuring that medicines and medical devices work, and are acceptably safe. The MHRA is an executive agency of the Department of Health.

Aims
Protecting public health through regulation, with acceptable benefit-risk profiles for medicines and devices.

Promoting public health by helping people who use these products to understand their risks and benefits. Improving public health by encouraging and facilitating developments in products that will benefit people.

Objectives

safeguard public health through our primary role in ensuring that the products we regulate meet required standards, that they work and are acceptably safe carry out our communication role through the provision of accurate, timely and authoritative information to healthcare professionals, patients and the public support research, ensuring through the application of Better Regulation principles that regulation does not stifle innovation influence the shape of the future regulatory framework through use of our effective European and International relationships run an organisation with a skilled and equipped workforce that is fit for the future.

Activities
assessing the safety, quality and efficacy of medicines, and authorising their sale or supply in the UK for human use overseeing the UK Notified Bodies that audit medical device manufacturers operating post-marketing surveillance and other systems for reporting, investigating and monitoring adverse reactions to medicines and adverse incidents involving medical devices and taking any necessary action to safeguard public health, for example through safety warnings, removing or restricting the availability of products or improving designs
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operating a proactive compliance programme for medical devices operating a quality surveillance system to sample and test medicines and to address quality defects, monitoring the safety and quality of imported unlicensed medicines and investigating Internet sales and potential counterfeiting of medicines regulating clinical trials of medicines and medical devices monitoring and ensuring compliance with statutory obligations relating to medicines and medical devices through inspection, taking enforcement action where necessary; promoting good practice in the safe use of medicines and medical devices managing the General Practice Research Database (GPRD) and the British Pharmacopoeia (BP) and contributing to the development of performance standards for medical devices; offering scientific, technical and regulatory advice on medicines and medical devices providing the public and professions with authoritative information to enable informed dialogue on treatment choices. These activities are supported by our ten divisions who are also responsible for: information management providing executive support services; human resources; and finance.

How MHRA regulate

The main difference between how medicines and medical devices are regulated lies in how a product gets onto the market. All medicines are directly approved by the MHRA which issues a 'marketing authorisation', or licence. Manufacturers and distributors are also licensed directly by MHRA. Medical devices are approved by private sector organisations called 'Notified bodies'. Their approval is needed before a CE mark ["Conformit Europenne" ("European Conformity")] can be put on the device, though the manufacture of low risk devices is simply registered with the MHRA. The MHRA audits the performance of Notified Bodies. However: when a product is on the market and in use, there are more similarities than differences in the ways medicines and devices are regulated there are similar systems for receiving reports of problems with products and similar ways of issuing warnings if problems are confirmed after investigation there are also similar systems for inspection of manufacture to ensure that companies are complying with regulations, and similar ways of enforcing the law if that proves necessary.

Safety information
No product is ever risk free. Some of the risks are known about when a medicine is first licensed or medical device first used. However, some information only comes to light later as more people use the products. This section includes current and historic alerts, messages and advice and guidance we have issued about products. This section also includes our safety reporting forms for medicines, medical devices and blood.

Safety warnings, alerts and recalls

This section includes current and historic:

drug alerts on defective medicines medical device alerts and their predecessors safety warnings and messages about medicines, including letters sent to health professionals.

Medical Device Alerts Medical Device Alerts (MDAs) were introduced on 1 January 2003, to replace the previous types of safety warnings (Hazard notice, Safety notice, Device alert, Advice notice and Pacemaker technical note) which can be found under Publications > Safety warnings. MDAs are distributed to the NHS (National Health Services) in England via the Department of Health's Central Alerting System (CAS). MDAs remain valid unless they are updated or withdrawn. They are reviewed once they are five years old (and subsequently every year) and the lists on this website are amended accordingly. Drug alerts This section of the site gives details of MHRA drug alerts issued since 29 October 2001. Manufacturers and importers are obliged to report to the MHRA any quality defect in a medicinal product which could result in a recall or restriction on supply. Other users and distributors of medicinal products are encouraged to do this. Where a defect is considered to be a risk to public health, the marketing authorisation holder withdraws the affected product from use and the MHRA issues a 'drug alert' letter. This alert is classified from 1 to 4 depending upon the risk presented to the public health by the defective product. Class 1 is the most critical, for example serious mislabelling, microbial contamination or incorrect ingredients, and requires immediate recall; Class 4 is the least critical and advises 'caution in use'.

Committees
In the public interest, ministers need the advice they receive on matters relating to the regulation of medicines and medical devices to be impartial. They also need to be able to seek such advice from a wide range of highly skilled professionals who are senior and well regarded in their respective fields and from a range of appointed lay and patient representatives. A number of independent advisory committees have been established to provide such an advice. These committees can also establish working group to address specific problems. Members of these committees receive no remuneration but are paid expenses. This section sets out details about the terms of references of these various committees, their members and the work they undertake.

Medicines advisory bodies

The medicines advisory bodies were introduced under the Medicines Act 1968. They provide advice to ministers (who are the Licensing Authority) on aspects of medicines regulation.

Devices
This section contains details of committees relating to the devices sector.

Independent Scientific Advisory Committee for MHRA database research

The ISAC is a non-statutory expert advisory body was established in 2006 by the Secretary of State to provide advice on research related requests to access data from the Yellow Card Scheme and the General Practice Research Database. Members are appointed by the Appointments Commission.

Conferences and Learning Centre

This section includes details of upcoming MHRA conference and events, as well as educational programmes for healthcare professionals about medicines and medical devices. It also gives information on how we can provide experienced MHRA speakers for your events.

Learning Centre
This section provides educational programmes for healthcare professionals about medicines and medical devices. The topics covered include: Pharmacovigilance Basic observations Devices in practice (basic principles of device purchasing and management) Electrosurgery (diathermy) Anaesthetic machines Operating table

Request a speaker
MHRA speakers are renowned worldwide for their knowledge and expertise in Pharmaceutical and Medical Device Regulation and regularly participate in both high profile international events and smaller low key events. We can provide you with experienced speakers to match your event needs and enhance your event programme.

ONLINE SERVICES
This section provides access to a range of online services. You can sign up for free email notifications when new content is published on the MHRA website, report safety problems and make online requests under the Freedom of Information Act. There is also access to Drug Analysis Prints (listings of suspected adverse drug reactions reported to us) and details of our subscription services such as RamaXL.

PUBLICATIONS
We produce a range of publications, most of which are aimed at healthcare professionals or people working in the device or pharmaceutical industries. Some are available in full text as pdf documents.

NEWS CENTRE This section provides details of new items added to the site as well as a full archive of our press releases and statements. It also includes our Press Office contacts and a photo and image library of downloadable images suitable for print output.

YOUR VIEWS
This section gives you the opportunity to tell us your views. It includes our public consultations, website feedback forms (general and technical) and how you can make a complaint to us.

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OVERALL PROCESS OF AN MHRA INSPECTION

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PREPARING FOR THE INSPECTION

The purpose of the statutory inspection is to examine the systems used by the University in the conduct of CTIMPs. The MHRA will be interested in processes relating to Regulatory submissions, Laboratories, IMP management, Contract Management, Project management, Trial-file management, Quality Assurance, Training, Computer systems, Monitoring, Pharmacovigilance, Medical Advisors, Data management, Statistical Analysis, Report writing, Archives and Investigational sites. The MHRA will be interested how these processes work in practice to ensure that: - robust procedures are in place - the rights, wellbeing and safety of trial participants are protected - the trial is conducted in accordance with the principles of GCP - appropriate Standard Operating Procedures (SOPs) are in place and that these are clearly documented and adhered to e.g. Reporting of SAEs and SUSARs. - trials have all the necessary approvals prior to commencing. Relevant authorities may include relevant ethics committee, Sponsor, MHRA, Host R&D office and other trial sites etc. - adequate pharmacovigilance is in place

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POST INSPECTION
Within 30 working days of the end of the MHRA inspection, the MHRA will issue a report to the Sponsor and they will categorise their findings into three areas such as Critical, Major and/or Other. The MHRA will expect responses to be received within 30 calendar days of despatch. The response to the MHRA will be managed by RACD. Once the MHRA are satisfied with our response, they will issue a summary letter and an inspection certificate.

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MARKETING AUTHORIZATIONS (PRODUCT LICENCE) The MHRA operates a system of licensing before the marketing of medicines. Medicines which meet the standards of safety, quality and efficacy are granted a marketing authorisation (previously a product licence), which is normally necessary before they can be prescribed or sold. This authorisation covers all the main activities associated with the marketing of a medicinal product. This section gives an overview of the process for obtaining a marketing authorisation in the United Kingdom. Who can apply? Applications are generally submitted by the pharmaceutical industry, but anyone with the necessary supporting data may apply for a licence. The legal framework Applicants need to be aware of the relevant EC and UK primary legislation and subsidiary documentation. The life cycle of a new medicine begins with discovery and laboratory studies carried out by the pharmaceutical company. During this period, studies will be conducted on the mode of action of the drug, how it moves around the body and its safety. The MHRA has no interest in these early stages of development until the company wants to start clinical trials in patients. It is at this stage of development that the company will have sufficient evidence to indicate whether the product is going to be a licensable medicine. Purpose of the application The applicant will be hoping to obtain a marketing authorisation as quickly as possible. To minimise delays, it is important that adequate information is provided to demonstrate that the product is of adequate quality for its intended use, that it is sufficiently safe and that it is effective. No other factors are considered when assessing the application (for example, comparative efficacy or cost benefit). Types of application There are a number of different types of application, depending on the nature of the active ingredient of the product. These vary from applications for products containing new active substances, those whose active ingredients have previously been evaluated before, known as abridged applications, to those biological and biotechnology products manufactured by recombinant DNA technology, products where genetic manipulation of cells is required, or a monoclonal antibodies. Submitting the application: All applications must follow the common technical dossier (CTD) format which has been a requirement since 2003. The preferred format for new marketing authorisation (MA) applications is the electronic Common Technical Dossier (eCTD). However, we accept that many companies
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are not yet ready to submit applications in that format. Therefore, we will accept applications in PDF-only format. The Summary of Product Characteristics (SmPC) will need to be prepared using the Word template. You also need to use the MHRA Adobe Application form which is available via the MHRA Portal. This will produce an XML file that we will be able to upload directly into our database. eCTD applications must be created according to the current specifications: eCTD specification v 3.2, EU Module 1 specification v 1.0, eCTD EU application v 1.0. Fees Licence applications Marketing authorisations (including extension applications) Major National ree (including hybrid applications) Decentralised procedure where UK is CMS Major (reduced in exceptional circumstances1 or orders under Section 104/105) Outgoing Mutual Recognition (UK RMS) - 1st wave - 2nd wave Incoming Mutual Recognition (UK CMS) and European reference products Abridged complex National fee (including hybrid applications) Decentralised procedure where UK is CMS Outgoing Mutual Recognition (UK RMS) - 1st wave - 2nd wave Incoming Mutual Recognition (UK CMS) and European reference products Abridged standard National fee Fee Fully compliant eCTD

105,146 101,541 33,709

100,252 96,797 32,135

44,934 29,516 70,774

67,468

29,068 28,073

27,716 26,762

11,623 7,709 19,650

18,732

10,659

10,162
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Licence applications Fee Marketing authorisations (including extension applications) Decentralised procedure where UK is 10,294 CMS Outgoing Mutual Recognition (UK RMS) - 1st wave 4,628 - 2nd wave 3,855 Incoming Mutual Recognition (UK CMS) 7,200 and European reference products Abridged simple National fee 2,906 Outgoing Mutual Recognition (UK 2,769 RMS) Outgoing Mutual Recognition 2,769 (informed consent) - 1st wave 2,769 - 2nd wave 2,769 Duplicates for all of the above outgoing Mutual Recognition applications when undertaken at the same time as the lead application

Fully compliant eCTD 9,812

6,864

2,771 -

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Forms

Marketing authorisation application forms Marketing authorisation - application for renewal Marketing authorisation - application for variation Marketing authorisation - application for change of ownership Marketing authorisation - parallel importing Marketing authorisation - parallel importing (variation) Sample for a product licence appliation
Validation Before assessment of the application can begin, validation takes place. The forms are checked for completeness and appropriate signatures. The dossier is checked for pagination and the inclusion of English summaries.

Professional assessment When an application has been validated it is placed in a queue for professional assessment. There are a number of different queues depending on the type of product and whether the application was made via the European route or direct to the MHRA. Assessors The role of the assessor is to determine whether, in their professional opinion, the applicant has provided adequate information to determine the product's quality, safety and efficacy, taking into account the claims made in the application forms. Before reaching an opinion they may need to discuss the data with the applicant or request additional information. Advisory bodies Applications for new active substances, novel delivery systems, the first generic version of an existing product and those applications where the assessor(s) are not satisfied with the information provided must be referred to the advisory bodies. The main advisory body for the evaluation of human medicines is the Commission on Human Medicines (CHM). A number of specialist subcommittees have been established to assist the CHM in its work. If an advisory committee advises the Licensing Authority to refuse an application, the applicant has the right to a hearing (written or oral) before the committee. If, after this, the committee still advises against granting a licence, the applicant has the right to appeal to the Person Appointed by the Licensing Authority.

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Renewals and variations to licences Marketing authorisations are granted for periods up to five years and have to be renewed at the end of this time. On renewal each marketing authorisation must reflect all the up to date knowledge about the product including any necessary action from the most recent periodic safety update report (PSUR). Variations to marketing authorisations are necessary to introduce changes to take account of technical and scientific progress, introduce additional safeguards, or reflect evolving therapeutic indications. It is common practice for new products to be varied many times, particularly in their first couple of years on the market.

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