The regulatory regimei Classification
The decision as to whether a product will be deemed a medicinal product, a medical device or other regulated product will largely depend on the particular intended use of the product, as assigned by the manufacturer, and on the demonstrated mode of action. In arriving at any decision with regard to classification, the applicant must provide the HPRA with sufficient information about the product and its intended usage, including all promotional material. This includes not only labels, leaflets and all advertising materials but also any websites linked to that literature. In the event that the HPRA determines that the product could potentially be a medicinal or other product, the product may be referred to the HPRA Classification Committee, which meets once a month and is responsible for assessing products for which classification is not obvious, including those that are borderline medical devices or medicinal products. Alternatively, classification requests for borderline products may be sent directly to the Classification Committee as opposed to being referred by the HPRA.
Decisions made by the Classification Committee can be appealed to the HPRA Management Committee, which may request the advice of the Advisory Committee on Human Medicines (ACHM) set up under the IMB Act. The decision of the Management Committee is final.ii Non-clinical studies
Non-clinical studies (e.g., non-interventional studies) are not regulated by the applicable laws and guidance for clinical trials in Ireland. They do not require the positive opinion of an ethics committee. There is, however, general legislation that applies, such as data protection legislation, the common law on consent for medical treatment and research, animal welfare protection laws and good laboratory practice.
Directive 2010/63/EU was transposed into Irish law in December 2012 by the European Union (Protection of Animals used for Scientific Purposes) Regulations 2012 (as amended). This legislation aims to improve the welfare of animals used for scientific purposes and to promote the principles of the three Rs – replacement, reduction and refinement:
- Replacement refers to the use of alternative methods that substitute the use of animals for scientific purposes. Where replacement is not possible, animal use must only be permitted where justified and where the expected benefits outweigh the potential adverse effects.
- Reduction measures must be applied so as to minimise the number of animals used in each research project.
- Refinement measures must also be applied to enable procedures to be carried out in the most humane manner possible and to minimise pain, suffering, distress and lasting harm.
The European Communities (Good Laboratory Practice) Regulations 1991 (as amended) give effect to Commission Directive 2004/10/EC, which requires certain testing on chemicals to be carried out in accordance with the principles of Good Laboratory Practice. The Irish National Accreditation Board has statutory responsibility for enforcement of these regulations.iii Clinical trialsMedicinal products
Clinical trials in Ireland are regulated by the European Communities (Clinical Trials on Medicinal Products for Human Use) Regulations 2004 to 2009 (the Clinical Trial Regulations), which implement Directive 2001/20/EC on the conduct of clinical trials (the Clinical Trials Directive) and Directive 2005/28/EC on good clinical practice for medicinal products for human use (the GCP Directive).
The Clinical Trial Regulations apply to clinical trials conducted with human subjects and involving investigational medicinal products (IMP). On 16 April 2014, the new Clinical Trials Regulation was adopted. It will repeal the Clinical Trials Directive and its aim is to simplify and harmonise the authorisation of clinical trials across the European Union. The new Regulation is expected to enter into force six months after a new EU database and single online EU portal created under the new Regulation become fully functional. Clinical trials will, however, continue to be conducted in accordance with the Clinical Trials Directive until the new Regulation becomes applicable.Authorisations
A clinical trial authorisation (CTA), issued by the HPRA, must be obtained by a sponsor or person authorised to act on his or her behalf prior to commencing a clinical trial. An investigational medicinal product dossier should be submitted to the HPRA providing clinical and non-clinical supporting data for the investigational medicinal product, with evidence of the favourable ethics committee opinion and the sponsor's EudraCT number (see 'Trial preconditions', below).Informed consent
The sponsor must obtain each trial subject's informed consent and inform each trial subject of the trial procedure and his or her right to withdraw at any time. Other conditions apply with respect to the requirements of the applicable data protection legislation and the Clinical Trials Regulations. Documentation relating to these matters must be submitted to the ethics committee for opinion before the application for a CTA is made to the HPRA (see below).Trial preconditions
The following items must be satisfied before a clinical trial can commence:
- the sponsor, or the person authorised to act on his or her behalf in relation to the trial, is established in the European Union;
- the sponsor has registered with the European Economic Area (EEA) system for monitoring drug safety, EudraVigilance;
- a favourable ethics committee opinion in relation to the trial protocol has been obtained;
- the HPRA has granted a CTA; and
- insurance and indemnity cover for the conduct of the trial has been obtained.
To facilitate the effective initiation of clinical trials and the removal of administrative barriers, a single HSE clinical trial indemnity form (CTIF) has been agreed between the State Claims Agency and the Irish Pharmaceutical Healthcare Association (IPHA) for the conduct of industry-led clinical trials in Ireland. The CTIF is applicable to the conduct of any industry-sponsored clinical trial in any state hospital in Ireland. Use of the HSE CTIF, which refers to the IPHA clinical trial compensation guidelines, provides the assurance that the company sponsoring a clinical trial will, without legal commitment, adhere to certain guidelines in the event of injury caused to a patient that is attributable to participation in the trial in question.Medical devices
Devices carrying the CE mark may be freely marketed anywhere in the European Union. Clinical assessments are usually required before non-CE marked medical devices may enter the Irish market. For any clinical investigation to commence in Ireland, approval from the HPRA is required, with a positive opinion of an ethics committee. Certain clinical investigations, such as those using CE-marked devices within their intended purpose, may not require a review by the HPRA. This must be assessed on a case-by-case basis.
Typically, applications are submitted by a commercial sponsor, such as a medical device manufacturer. By this application, the manufacturer is proposing to conduct an investigation to gather the necessary clinical data to demonstrate the basic safety and performance of their device. The requirements governing the conduct of clinical investigations are laid down in Directive 93/42/EEC and in the IVD Directive, as well as various Commission guidance documents (MEDDEVs) and international standards. The HPRA reviews the regulatory, technical and clinical aspects of the application. The HPRA reviews applications to conduct clinical investigations in Ireland in parallel with the appropriate ethics committee review. An initial decision will be issued within 30 days of the application being made, and the final decision will be provided by the HPRA within 60 days of the application.iv Named-patient and compassionate-use proceduresMedicinal productsNamed-patient programmes
Regulation 2 of Schedule 1 of the Marketing Regulations regulates named-patient programmes in Ireland. Under the Marketing Regulations, a named-patient programme permits the sale or supply of an unauthorised product in response to a bona fide unsolicited order, formulated in accordance with the specifications of a practitioner for use by his or her individual patients on his or her direct personal responsibility, to fulfil the special needs of those patients.
To make use of the programme, the following conditions must be satisfied:
- receipt of an unsolicited order from a registered healthcare professional (HCP);
- the product must be supplied to the order or prescription of the requesting HCP;
- the product is only provided to the HCP's individual patient; and
- the provision of the product is supervised under the direct personal responsibility of the HCP.
There is no formal authorisation for establishing a named-patient programme in Ireland. However, wholesalers and manufacturers that receive or import exempt medicinal products intended for distribution in Ireland under a named-patient programme must notify the HPRA of this fact within two working days of receipt of the consignment. There are a number of exceptions to this notification requirement, all of which depend on the specific supply chain in question. Packaging and labelling requirements will apply, as well as fees and record-keeping obligations in terms of pharmacovigilance and quality defects.Compassionate use
Medicinal products for use in an authorised clinical trial are exempt from the requirement to be subject to a marketing authorisation (MA). The HPRA does recognise the option of an Expanded Access Programme (EAP) for patients who have been treated with a medicinal product during a clinical trial and wish to continue treatment after the trial is completed. If, however, the EAP fulfils the definition of a clinical trial, it is required to be authorised as such under the applicable Irish legislation. In the event that it does not fulfil the definition of a clinical trial, the medicinal product can only be supplied via a named-patient programme. This essentially means that EAPs for groups of patients at a time are only recognised in Ireland if they are authorised as clinical trials and meet all applicable legislation governing clinical trials.Medical devices
The CE marking does not have to be present on medical devices intended for clinical investigations, custom-made devices and in vitro diagnostic medical devices for performance evaluation. The CE marking does not have to be present on medical devices intended for exhibitions, demonstrations, trade fairs, etc. However, these devices must bear a visible marking indicating that they are not intended to be marketed or put into use.v Pre-market clearanceMedicinal products
The placing of medicinal products on the market in Ireland is regulated by the Marketing Regulations. Subject to certain exceptions, a medicinal product cannot be placed on the market in Ireland unless an MA has been granted for that product by the HPRA or the European Commission. An MA can be obtained through the following procedures:
- National procedure: an application is submitted to the HPRA and, if granted, the MA entitles the marketing authorisation holder (MAH) to place the medicinal product on the Irish market.
- Mutual recognition procedure: if the medicinal product has received an MA in another EEA Member State (the Reference Member State), the MAH can apply to one or more other Member States (the Concerned Member States) to recognise that authorisation. If a product has received an MA in another Member State, the MAH can apply to the HPRA to mutually recognise that authorisation in Ireland.
- Decentralised procedure: this can be used if the product has not yet received an MA in a Member State and the applicant wishes to apply for simultaneous authorisation in two or more Member States. The applicant nominates one of the states as the Reference Member State, whose competent authority examines the application in full and prepares a report for the competent authorities of the Concerned Member States. The HPRA is the competent authority in Ireland for these applications.
- Centralised procedure: a Community MA, which is valid throughout the EEA, can be obtained by applying to the European Medicines Agency (EMA), through the centralised procedure governed by Regulation (EC) No. 726/2004, as amended, on the authorisation and supervision of medicinal products, and establishing a European Medicines Agency (as amended) (the EMA Regulation). Following a positive assessment by the EMA, an MA is granted by the European Commission. The centralised procedure is compulsory for certain medicinal products.
The conformity assessment and CE marking procedures for medical devices discussed in the European Union chapter also apply in Ireland. Apart from the registration requirement below, there is little additional regulatory pre-market review and approval by the HPRA.
The Medical Device Regulations require that certain persons placing devices on the market must register their contact details and details of their devices with the HPRA. This requirement applies if that person has a registered place of business in Ireland and if that person:
- manufactures Class I or custom-made medical devices and places them on the market under his or her own name or trading name;
- manufactures custom-made, active, implantable medical devices and places them on the market under his or her own name or trading name;
- manufactures in vitro diagnostic medical devices and places them on the market under his or her own name or trading name;
- fully refurbishes Class I devices or labels one or more ready-made devices, with a view to placing these on the market under his or her own name;
- places medical devices bearing the CE marking on the market, in a system or a procedure pack;
- sterilises, for the purpose of placing on the market, systems or procedure packs or other CE-marked medical devices designed by the manufacturers to be sterilised before use; or
- is the designated European authorised representative for a manufacturer that does not have a registered place of business in the European community, and that places on the market devices within the above-listed categories.
An application for authorisation of a generic of a medicinal product or similar biological product can be made to the HPRA eight years after authorisation of the reference product (i.e., the original product) when the period of data exclusivity for the reference product expires. If the application for the reference product was made before 30 October 2005 and the application was not in respect of a Community MA, the period is reduced to six years.
Once authorised, a generic or similar biological product cannot be placed on the market for 10 years (depending on the exclusivity period available for the reference medicinal product) following authorisation of the reference product. This is extended to 11 years if, during the first eight years after the initial MA for the reference product is granted, the holder of that MA is granted an authorisation for a new therapeutic indication of significant clinical benefit in comparison to existing therapies.Medical devices
There is no specific regulatory exclusivity for medical devices in Ireland. Medical devices may be protected by a patent granted by the Irish Patents Office under the Patents Act 1992 (as amended) (the Patents Act). Patents granted under the Patents Act can be for 20 years (full-term patent) or 10 years (short-term patent).vii Post-approval controlsMedicinal products
The Irish requirements concerning post-approval controls reflect those discussed in the European Union chapter.Additional information to the HPRA
In addition to the requirements for MAHs discussed in the European Union chapter, MAHs are required by the Marketing Regulations to provide the HPRA with certain information, including the date that the medicinal product is placed on or removed from the market, and any new information that may influence the evaluation of the benefits and risks of the medicinal product.Transfer of marketing authorisations
An MA may be transferred from the existing authorisation or licence holder to another holder using a transfer procedure. A transfer may occur before a product is authorised or after authorisation, to a company related to the existing holder or to an unrelated company. An MA can be transferred within six weeks of receipt of a valid application by the HPRA. Products can be transferred either before authorisation or once authorised. Transfer applications are subject to the national procedure, even if the product has been authorised via the mutual recognition procedure.Medical devices
The Irish requirements concerning post-approval controls reflect those discussed in the European Union chapter.viii Manufacturing controlsMedicinal products
Manufacturing is regulated by the Medicinal Products (Control of Manufacture) Regulations 2007 (as amended).
The manufacture and importation of medicinal products is subject to the holding of an authorisation. This is known as a manufacturing import authorisation (MIA). To obtain an MIA, an application is made to the HPRA. The manufacturer is required to provide certain documentation as part of the application that will be verified for accuracy by the HPRA, which may include an inspection of the site where the activities take place. There is no restriction on foreign applicants applying for an MIA. However, the HPRA only issues manufacturing authorisations for Irish manufacturing or importation sites. Applications must be granted or refused by the HPRA within 90 days.
The requirements governing the information to be submitted as part of the application and those required to ensure the validity of the authorisation (e.g., a qualified person and the principles of good manufacturing practice (GMP)) are discussed in the European Union chapter.
The HPRA is responsible for monitoring compliance with MAs and GMP requirements. To this end, the HPRA can:
- enter and inspect sites;
- inspect and copy records;
- conduct tests or examinations at the site; and
- take samples for testing.
The HPRA can investigate whether a manufacturer or importer has obtained an authorisation and is complying with it, and has, at his or her disposal, a qualified person who meets the requirements and is fulfilling his or her obligations.Medical devices
Apart from the registration requirement discussed in Section II.v, the Irish requirements concerning the manufacture of medical devices are similar to those discussed in the European Union chapter.ix Advertising and promotionMedicinal products
The advertising of medicinal products is regulated by the Medicinal Products (Control of Advertising) Regulations (the Advertising Regulations). The Advertising Regulations are enforced by the HPRA. Non-compliant advertisements can be required to be withdrawn and the person responsible for the advertisement may be required to publish a corrective statement. Breach of the Advertising Regulations is a criminal offence under the IMB Act. The Consumer Protection Act 2007 and the European Communities (Misleading and Comparative Marketing Communications) Regulations 2007 also apply to general advertising and commercial practices.
Self-regulation plays an important role and members of the IPHA must comply with the Code of Practice for the Pharmaceutical Industry (the IPHA Code) for prescription and non-prescription medicinal products, and the Code of Standards of Advertising Practice for the Consumer Healthcare Industry (the IPHA Consumer Code) for non-prescription medicinal products.
The IPHA Code fully reflects the standards of the European Federation of Pharmaceutical Industries and Associations Code on the Promotion of Prescription-only Medicines to, and Interactions with, Healthcare Professionals. The IPHA Code and the IPHA Consumer Code apply only to those pharmaceutical companies that have voluntarily agreed to be members of the IPHA. The Irish Generic Medicines Association (IGMA), the industry body representing manufacturers of generic medicinal products, has published the Code of Practice on Advertising of Medicinal Products, a similar code based on the Regulations and the Directive.
The Advertising Standards Authority for Ireland (ASAI) has published a Manual of Advertising Self-Regulation with the Code of Standards for Advertising, Promotional and Direct Marketing in Ireland (the ASAI Code). The ASAI Code applies to the advertising of medicinal products, with the exception of specialised marketing communications addressed to the medical, veterinary and allied professions. The Broadcasting Authority of Ireland has produced a General Commercial Communications Code, which applies to advertising broadcasts on radio or television channels licensed in Ireland.Medical devices
The Medical Devices Legislation does not specifically regulate the advertising of medical devices.
The Irish Medtech Association Code of Ethical Business Practice (the Medtech Code) is a self-regulatory code and is binding on all members of the Irish Medtech Association (formerly IMDA). This Code is not underpinned by legislation.
The Medtech Code has been developed by the Irish Medtech Association and is largely based on that of MedTech Europe (formerly Eucomed and the European Diagnostic Manufacturers Association), the European medical technology industry association. A new common Code of Ethical Business Practice was adopted by MedTech Europe, in a move to put forward clearer and more stringent self-regulation. The new Code replaces the current codes of business practice and is known as the MedTech Europe Code of Business Practice, which became binding for Irish Medtech Association members on 1 January 2018. It sets the minimum standard by which industry members operate across Europe.x Distributors and wholesalersMedicinal productsWholesaler's distribution licence
The wholesale or distribution of medicinal products is subject to the possession of a wholesale distribution licence (WDL), as outlined in the Medicinal Products (Control of Wholesale Distribution) Regulations 2007 to 2013. The relevant competent authority in Ireland is the HPRA. The activities that require a WDL are as follows:
- 'procuring' is understood as obtaining, acquiring, purchasing or buying medicinal products from manufacturers, importers or other wholesale distributors;
- 'holding' is understood as storing medicinal products; and
- 'supplying' is understood as all activities of providing, selling, donating medicinal products to wholesalers, pharmacists, or persons authorised or entitled to supply medicinal products to the public.
There is no specific authorisation for the wholesale or distribution of medical devices in Ireland.xi Classification of productsMedicinal products
Prescription-only medicinal products can only be dispensed by a person lawfully conducting a retail pharmacy business, and must be dispensed by or under the personal supervision of a registered pharmacist according to a prescription issued by a registered medical practitioner, a registered dentist or, in certain circumstances, a registered nurse.
Certain non-prescription drugs (as set out in the Medicinal Products (Prescription and Control of Supply) Regulations 2003, as amended) can be sold only from a pharmacy under the supervision of a registered pharmacist. General sale products can be placed on general sale, which means that they can be sold in a pharmacy and in any other outlet that is not a pharmacy, for example a supermarket.
The supply of prescription-only medicinal products in Ireland by mail order is prohibited. Supply by mail order is defined as both:
- any supply made, after solicitation of custom by the supplier, or by another person in the supply chain inside or outside Ireland; and
- without the supplier and the customer being simultaneously present and using a means of communication at a distance, whether written or electronic, to convey the custom solicitation and the order for supply.
There are no such similar restrictions on medical devices in Ireland.xii Imports and exports
The Irish rules governing the import and export of medicinal products and medical devices generally reflect those at EU level.
An MIA is required for the importation of medicinal products from outside the EEA into Ireland. Applications are made to the HPRA, and must include details of the:
- relevant medicinal products and pharmaceutical forms;
- proposed operations;
- premises, equipment and facilities; and
- site master file.
There must be a 'qualified person' for batch release, who ensures that each batch complies with the law, the GMP, the manufacturer's authorisation and the MA or equivalent. The qualified person must be nominated by the applicant. Each applicant must give a written undertaking to comply with the conditions of the authorisation, if granted.
Medicinal products may only be exported by authorised manufacturers or distributors who have obtained an MIA for these export activities.xiii Controlled substances
Medicinal products that contain controlled substances as set out in Misuse of Drugs Acts 1977 to 2016 and the Misuse of Drugs Regulations 1988 (as amended) require a controlled drug licence. In Ireland, controlled substances are listed in the Acts and the Regulations. Depending upon which Schedule of the regulations the controlled substance is listed in, a manufacturer may be required to obtain a controlled drug licence from the HPRA before the company can legally sell the products to third parties in Ireland. It can take between two and eight weeks to obtain a controlled drugs licence.xiv EnforcementMedicinal products
In most cases, a breach of the applicable medicinal product regulations constitutes a breach of Section 32 of the IMB Act, which means that the offending entity shall be guilty of an offence and liable to a fine or imprisonment, or both.
For a summary conviction, a fine not exceeding €2,500 or a term of imprisonment of one year, or both, may be imposed. In addition, on summary conviction, the district court has discretion to award costs to the HPRA. On indictment, for a first offence, a person shall be liable to a fine not exceeding €120,000 or a term of imprisonment not exceeding 10 years, or both. For a second or subsequent offence, a fine not exceeding €300,000 or a term of imprisonment not exceeding 10 years, or both, may be imposed. A Section 32 offence can be prosecuted by the Minister for Health, the HPRA, the Pharmaceutical Society of Ireland or the health board in whose functional area the offence was committed. If an offence is committed by a corporate body and is proven to have been committed with the consent or 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.
If there is a breach of the self-regulatory IPHA Code, the IPHA Code Council, which is responsible for overseeing breaches, may decide to:
- ask the company concerned to cease the practice found to be in breach of the IPHA Code and take all necessary steps to avoid a similar breach in the future;
- reprimand the company for the breach of the IPHA Code;
- order the recovery of material found to have been in breach of the IPHA Code;
- order the correction of inaccurate information by way of direct contact with the relevant HCPs or by publication, in the medical or pharmaceutical press, of a corrective notice in terms approved by the IPHA Code Council and Appeals Board;
- order the immediate publication of the decision in whole or in part and specify how and to whom the decision is to be sent. This is in addition to the inclusion of details of the decision in the annual Code of Practice Publication of Findings Report;
- refer the matter to the Minister for Health, in the case of difficult or persistent breaches of the IPHA Code; or
- recommend to the IPHA Board of Directors that the offending party be suspended or expelled from the IPHA.
Administrative fees may also be charged. All findings are published at least once a year and are made available to:
- all members of the IPHA;
- all non-IPHA member Code signatories;
- the Minister for Health or Department of Health; and
- the HPRA.
If an authorised officer appointed by the HPRA has reasonable grounds for suspecting that an offence under the Medical Device Regulations has been committed on any premises, he or she may seek a search warrant from the district court to search those premises. Any person or body corporate found guilty of an offence under these Regulations shall be liable on summary conviction to imprisonment for up to six months or a fine, or both. When an offence is committed by a body corporate with the consent, connivance or by the negligence of any person who is a director, manager, secretary or other officer of that body corporate, that person may also be personally liable.
If there is a breach of the self-regulatory Irish Medtech Code, the Board of the Irish Medtech Association responsible for overseeing breaches may decide to:
- issue a formal letter of reprimand to the member company;
- issue a formal letter of reprimand to the member company and also recommend to suspend that member company from membership of the Irish Medtech Association for a specified period or to impose conditions for readmission; or
- recommend to expel the offender from the Irish Medtech Association.
Administrative fees may also be charged.