REGULATORY OVERVIEW

1. What is the regulatory framework for the authorisation, pricing and reimbursement of drugs, biologicals and devices (as they are termed in your jurisdiction)?

Legislation

Medicinal products. The regulatory framework for medicinal products in Ireland is based on Directive 2001/83/EC on the Community code relating to medicinal products for human use (as amended) (Code for Human Medicines Directive). This was implemented in Ireland by the Irish Medicines Board Act 1995 (as amended) (IMB Act) and domestic regulations, most notably the Medicinal Products (Control of Placing on the Market) Regulations SI 540/2007 (as amended) (Marketing Regulations).

Pricing and reimbursement of medicinal products. A Framework Agreement between the Irish Pharmaceutical Healthcare Association (IPHA), an organisation representing the international research-based pharmaceutical industry in Ireland, the Department of Health and the Health Services Executive (HSE) came into effect on 1 November 2012 (see Questions 3 and 4).

Medical devices. The regulatory framework for medical devices is contained in the following, as transposed into Irish law (Medical Devices Legislation):

  • Directive 93/42/EEC concerning medical devices (as amended).
  • Directive 90/385/EEC on active implantable medical devices (as amended).
  • Directive 98/79/EC on in vitro diagnostic medical devices (IVD Directive) (as amended).

Regulatory authorities

The Irish Medicines Board (IMB) (see box, Regulator details) is the competent authority responsible for regulating medicinal products and medical devices. The IMB is a statutory body created by the IMB Act. The NSAI is the notified body in Ireland approved by the IMB to carry out conformity assessment procedures to ensure compliance with medical devices legislation.

Biotechnology and combination products

All medicinal products for human use derived from biotechnology and other high technology processes must be approved by the European Medicines Agency (EMA).

Regulations on the contained use or deliberate release of genetically modified organisms (GMOs) in Ireland are implemented by the Environmental Protection Agency.

Medical devices incorporating a medicinal product are regulated by the IMB under the medicinal products and medical devices legislation detailed above. They are classified as Class III (highest risk) devices and are therefore subject to high levels of compliance assessment.

PRICING AND STATE FUNDING

2. What is the structure of the national healthcare system, and how is it funded?

The Health Act 1970 (as amended) sets out the statutory basis for the structure of the national healthcare system. The public healthcare system is funded by the state through taxation and social security contributions. Private healthcare is funded by private insurance, social security schemes and private funds.

The Department of Health determines healthcare policy and expenditure. This is implemented by the HSE which was established by the Health (Amendment) Act 2004. The HSE integrates the delivery of health and personal social services through three service delivery units, namely:

  • Population Health, which promotes and protects public health, and is responsible for immunisation programmes, infection control and environmental health.
  • Primary, Community and Continuing Care, which delivers health and personal social services in the community (with the exception of acute hospitals).
  • National Hospitals Office, which provides acute hospital, ambulance and other pre–hospital emergency response services throughout the country.

There are three categories of hospitals in Ireland:

  • HSE hospitals, which are owned and funded by the HSE.
  • Voluntary public hospitals, which are owned by private bodies but which receive state funding.
  • Private hospitals, which are owned by private bodies and receive no state funding.

The Health Information and Quality Authority within the HSE (HIQA) is responsible for regulating and accrediting public hospitals, implementing quality assurance programmes, and evaluating the clinical and cost effectiveness of health technologies. The Corporate Pharmaceutical Unit within the HSE is responsible for evaluating the schemes operated by the HSE for the provision of drugs and medical devices to patients, in conjunction with the National Centre for Pharmacoeconomics (NCPE).

3. How are the prices of medicinal products regulated?

There is no specific legislation currently in force regulating the pricing of medicinal products. The Health (Pricing and Supply of Medical Goods) Bill 2012 has been proposed in the Irish parliament, although it is not yet clear when it will be passed into law (see Question 35).

A framework agreement between IPHA, the Department of Health and the HSE (Agreement) came into effect on 1 November 2012 and will operate for three years. It governs the pricing and supply of branded medicines that are reimbursed by the state through the reimbursement schemes, or that are supplied to state funded hospitals and agencies. It is envisaged that a separate agreement will be entered into between the Department of Health, HSE and the Association of Pharmaceutical Manufacturers in Ireland (APMI), the industry body representing manufacturers of generic medicinal products, in the near future.

The pricing provisions of the Agreement include a price freeze, whereby the price of medicines covered by the Agreement will not increase, save for exceptional circumstances, during the term of the Agreement. New medicines introduced in Ireland during the term of the Agreement will be priced at the currency-adjusted average price to the wholesaler of the medicine in certain nominated EU member states. If a Health Technology Assessment (HTA) has been deemed necessary and a lower price was submitted with the HTA application, the lower price will apply. Where the medicine is not available in any of the nominated EU member states, the price will be agreed between representatives of the manufacturer/importer of the medicinal product and the HSE.

The Agreement provides for a number of price reductions for patent expired medicines when the identical pharmaceutical form of the medicine approved by the IMB or the Commission becomes available for prescription within the reimbursement schemes or is supplied to state funded hospitals, the HSE or other state agencies.

The Agreement also includes a downwards-only price realignment for patented medicines, and for off-patent medicines for which there is no identical pharmaceutical form available for prescription within the reimbursement schemes, to the currency-adjusted average price to the wholesaler in the nominated EU member states in which the medicine is available.

4. When is the cost of a medicinal product funded by the state or reimbursed to the patient? How is the pharmacist compensated for his dispensing services?

Medicinal products dispensed in the community are funded by the state, through reimbursement of the pharmacist, where the patient in question is eligible under one of the reimbursement schemes, and where the medicinal product being dispensed is eligible for reimbursement.

Reimbursement schemes

The HSE Primary Care Reimbursement Service (PCRS) operates a General Medical Services (GMS) Scheme in addition to a number of other community reimbursement schemes (Community Drug Schemes) under which it reimburses primary care contractors, including pharmacists, for the cost of providing health services and medicines to the public.

The GMS Scheme provides free general medical services, including access to doctors, surgeons, dentists and medicines, to those who cannot afford such services. The Community Drug Schemes include the Drugs Payment Scheme, the Long Term Illness Scheme, the High Tech Drugs Scheme and the European Economic Area Scheme, among others.

Reimbursement procedure

A medicinal product is eligible for reimbursement if it:

  • Has a current MA.
  • Is approved for reimbursement by the HSE.
  • Is prescribed by a doctor.
  • Is dispensed by a doctor or pharmacist.

New medicines for which an MA has been granted may become reimbursable within 75 days of application to the HSE for reimbursement approval, subject to certain exceptions. New and existing technologies that are of high cost or that may have a significant impact on the Irish healthcare budget may be referred by the HSE for pharmacoeconomic assessment.

Payments to pharmacists are regulated by HSE Community Pharmacy Contractor Agreements and the Health Professionals (Reduction of Payments to Community Pharmacy Contractors) Regulations 2011 SI 300/2011.

MANUFACTURING

5. What is the authorisation process for manufacturing medicinal products?

Manufacturing is regulated by the Medicinal Products (Control of Manufacture) Regulations 2007 (as amended) (Manufacturing Regulations), which implement:

  • Title IV of the Code for Human Medicines Directive as amended by Directive 2011/62/EU on falsified medicinal products (Falsified Medicines Directive).
  • Article 13 of Directive 2001/20/EC on the conduct of clinical trials (Clinical Trials Directive).
  • Chapter 3 of Directive 2005/28/EC on good clinical practice for medicinal products for human use (GCP Directive).

Application

A manufacturing authorisation is required for the manufacture, dividing up, packaging, labelling, presentation and importation of medicinal products from outside the European Economic Area (EEA). Applications are made to the IMB, and must include details of the:

  • Applicant.
  • Relevant medicinal products and pharmaceutical forms.
  • Proposed operations.
  • Premises, equipment and facilities.
  • Site master file.
  • "Qualified person", who ensures that each batch complies with law, the manufacturer's authorisation and the MA or equivalent. (Such person must be nominated by the applicant.)

Each applicant must give a written undertaking to comply with the conditions of the authorisation, if granted.

Conditions

Applicants must have suitable and sufficient premises, equipment and facilities, and appropriate and sufficient staff, including the qualified person (see above, Application). The IMB can grant, refuse or conditionally grant an authorisation.

An authorisation only applies to the following, specified in the application and in relation to which it has been granted:

  • Medicinal products and pharmaceutical forms.
  • Manufacturing or importation operations.
  • Premises.

The manufacturer must not use the premises for any other purpose, and must comply with good manufacturing practice (GMP) and good distribution practice (GDP) (where applicable). The IMB must be informed of any change in qualified person or any particulars supplied in the application.

Restrictions on foreign applicants

There is no restriction on foreign applicants. However, the IMB only issues manufacturing authorisations for Irish manufacturing or importation sites.

Key stages and timing

Applications must be granted or refused by the IMB within 90 days. A request for further information by the IMB extends this period, and the expiry of 90 days does not mean that an implicit authorisation is granted. Applications to vary an authorisation due to a change to the medicinal products, pharmaceutical forms, premises or equipment or the manufacture, control or storage facilities must be granted or refused by the IMB within 30 days, unless an inspection is required. In this case, a decision is made within 90 days. All other decisions relating to variation applications are made within 60 days.

Fee

The application fee as of 1 January 2013 is EUR1,853. Annual renewal fees vary from EUR3,703 to EUR16,669, depending on the number of employees at the site. The variation fee is EUR274 for an administrative variation, and EUR768 for a technical variation. Current fees are available on the IMB website (www.imb.ie).

Period of authorisation and renewals

Authorisations are valid indefinitely, unless otherwise specified by the IMB. Authorisations granted before 23 July 2007 continue in force until their expiry date. Renewal applications for such authorisations should be submitted three months before the expiry date. Renewals will not carry an expiry date.

6. What powers does the regulator have in relation to manufacturing authorisations?

Monitoring compliance

The IMB is responsible for monitoring compliance with manufacturing authorisations, GMP and GDP requirements. The IMB can:

  • Enter and inspect sites.
  • Inspect and copy records.
  • Conduct tests or examinations at the site.
  • Take samples for testing.

The IMB can investigate whether a manufacturer or importer has:

  • Obtained an authorisation and is complying with it.
  • At his disposal the qualified person approved by the IMB who meets the requirements and is fulfilling his obligations.

The IMB can vary an authorisation at any time. The IMB can suspend or revoke the authorisation in total or in relation to certain medicinal products, on notice in writing to the authorisation holder, on certain grounds.

Imposing penalties

Breach of the Manufacturing Regulations is an offence under the IMB Act, resulting in:

  • On summary conviction, a fine up to EUR2,000 or imprisonment for up to one year, or both.
  • On conviction on indictment for a first offence, a fine up to EUR120,000 or imprisonment for up to ten years, or both, and for a subsequent offence, a fine up to EUR300,000 or imprisonment for up to ten years, or both.

If an offence is committed by a corporate body, and is proved to have been committed with the consent, connivance or is attributable to the neglect of any person who is an officer or shareholder (if the shareholder manages the corporate body), this person may be personally liable for the offence.

CLINICAL TRIALS

7. Outline the regulation of clinical trials.

Legislation and regulatory authorities

Clinical trials in Ireland are regulated by the European Communities (Clinical Trials on Medicinal Products for Human Use) Regulations 2004 to 2009 (Clinical Trial Regulations), which implement the Clinical Trials Directive and the GCP Directive.

The Clinical Trial Regulations apply to clinical trials conducted in human subjects and involving investigational medicinal products (IMP).

In July 2012, the Commission adopted a proposal to repeal the Clinical Trials Directive in order to simplify and harmonise the authorisation of clinical trials across the EU. Final adoption of the legislation is not expected before 2014 and it is not expected to come into effect before 2016.

Authorisations

A clinical trial authorisation (CTA), issued by the IMB, must be obtained by a sponsor or person authorised to act on his behalf prior to commencing a clinical trial. An investigational medical product dossier should be submitted to the IMB providing clinical and non-clinical supporting data for the trial together with evidence of the favourable ethics committee approval and the sponsor's EudraCT number (see below, Trial pre-conditions). Within 25 days of receipt of a valid application, the IMB gives written notice to the sponsor of its decision to:

  • Refuse the authorisation, setting out grounds for the refusal.
  • Grant the authorisation.
  • Grant the authorisation, subject to conditions.

If no notice is given, a clinical trial can be treated as if it has been authorised. Where the IMB refuses an authorisation or grants it subject to conditions, the sponsor can send an amended request to the IMB within 14 days. The IMB must respond within 60 days of the original request with one of the following actions:

  • Setting out the grounds for refusing the amended application.
  • Granting the amended application.
  • Granting the amended application subject to conditions.

The procedure differs for clinical trials involving certain medicinal products, such as for gene therapy and somatic cell therapy including xenogenic cell therapy, or containing genetically modified organisms.

Consent

The sponsor must obtain each trial subject's informed consent, and inform each trial subject of the trial procedure and his right to withdraw at any time. Consent should include consents to data processing. Documentation relating to these matters must be submitted to the ethics committee for approval before the application for a CTA is made to the IMB (see below, Trial pre-conditions).

Trial pre-conditions

The following items must be satisfied before a clinical trial can commence:

  • The sponsor, or the person authorised to act on his behalf in relation to the trial, is established in the EU.
  • The sponsor has registered with the EEA system for monitoring drug safety, EudraVigilance.
  • A favourable ethics committee opinion in relation to the trial protocol has been obtained.
  • The IMB has granted a CTA.
  • Insurance and indemnity cover for the conduct of the trial has been obtained.

If a CTA application involves a trial site in a third country, the IMB may require an undertaking from the sponsor or the owner of the premises to allow the premises to be inspected by or on behalf of the IMB, to ensure that GCP is followed.

If the trial relates to a genetically modified organism, a separate application must be made to the Environmental Protection Agency.

Procedural requirements

The trial must be conducted in accordance with GCP, and comply with:

  • The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals (ICH) Guidelines on GCP.
  • Commission Guideline ENTR/CT3 2006.
  • World Medical Association Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects 1964.

Annex 13 to the European Commission's GMP Guide on Manufacture of Investigational Medical Products.

The sponsor must:

  • Notify the IMB within seven days of any breach of GCP.
  • Ensure that all correct safety reporting is conducted, and that urgent safety measures are taken when there is an immediate hazard to health or safety.
  • Maintain a trial master file and retain all essential documents relating to the clinical trial for at least five years after its completion.
  • Notify the IMB of the end of the trial within prescribed time limits.

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This article was first published in the PLC Life Sciences Multi-Jurisdictional Guide 2013

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.