An intro to the legal situation for regulatory, pricing and reimbursement in Ireland. Prepared in association with Mason Hayes & Curran, a leading law firm in Ireland, this is an extract from The Pharma Legal Handbook: Ireland, available to purchase here for USD 99.

1. What are the regulatory authorities with jurisdiction over drugs, biologicals, and medical devices in your country?

The regulatory authority in Ireland for drugs, biological and medical devices in Ireland is known as the Health Products Regulatory Authority (HPRA). The HPRA is a state agency whose broad remit includes protecting and enhancing public and animal health by regulating medicines, medical devices, and other health products. In addition, it also monitors the safety of cosmetics.

The National Standards Authority of Ireland (NSAI) is the notified body in Ireland, and they are designated by the HPRA to carry out conformity assessment procedures to ensure compliance with all relevant legislation relating to medical devices. A notified body (NB) is an organisation designated by an EU country to assess the conformity of certain products before being placed on the market. NBs carry out tasks related to conformity assessment procedures set out in the applicable legislation, when a third party is required. A list of NBs is published by the European Commission.

The Health Services Executive (HSE) also plays a significant role in respect of drugs, biological and medical devices. It is charged with the provision of and running all the public health services in hospitals and communities in Ireland and is overseen by the Minister for Health.

2. What is the regulatory framework for the authorization, pricing, and reimbursement of drugs, biologicals, and medical devices?

1. Authorization

Medicines and Biologicals:

In the European Union (EU), all medicines must be authorised prior to their being marketed and being made available to patients. There are four different procedures that applicants can use in order to obtain a Marketing Authorisation (MA) depending on the type of medicine and the countries the product is going to be marketed in. The four procedures are:

• Centralised Application Process
• National Procedure
• Mutual Recognition Procedure
• Decentralised Procedure

Centralised Application Process:

Under the centralised authorisation procedure (CAP) applicants can make a single MA application to the European Medicines Agency (EMA); this method ensures that once granted by the European Commission (EC), the MA is valid in all EU Member States (MS). The legal framework is governed by Regulation (EC) No 726/2004. Medicinal products listed in the Annex to the Regulation must use this procedure for authorisation. The majority of new medicines in the EU obtain authorisation via CAP.

National Procedure:

Conversely, the majority of medicines already available in the EU were authorised at national level via national competent authorities (i.e. the HPRA in Ireland) after a full assessment. This procedure is not permitted where applicants already hold an MA in another MS. The HPRA grants MAs under the Medicinal Products (control of placing on the market) Regulations 2007. The HPRA in Ireland issues a MA along with a Product Authorisation (PA) number which is to be included on the box or container of the product. Details regarding applications are contained in EU Directive 2003/63/EEC and full applications must be submitted in accordance with a Common Technical Document (CTD) format.
If a company wishes to request an MA in several EU MS they can do so either using the Mutual – Recognition Procedure (MRP) (i.e. an MA granted in one MS can be recognised in others) or via the Decentralised Procedure (DCP) where a medicine or biological not yet authorised in the EU can be authorised simultaneously in several MS.

Mutual Recognition Procedure:

Under the MRP, a product is assessed by one MS known as a Reference Member State (RMS), and further on in the process, MAs can be sought from other MS who are known as Concerned Member States (CMS). CMS recognise the decision of the RMS rather than undertaking their own assessment process. Therefore the applicant will hold an MA in the RMS and all the CMS. If a medicinal product is required to be authorised under the CAP then this authorisation procedure cannot be used.

Decentralised Procedure:

The Decentralised Procedure (DCP) is used by applicants to apply for MAs in more than one MS where the product has not been authorised in any MS and where applicants do not want to use the CAP or the product is not eligible for the CAP.

The RMS does an initial evaluation of the product and issues a draft assessment report. The other CMS either agree with this initial evaluation or ask further questions or raise objections. If any potential issues are resolved, and each application is successful then each MS involved will issue an MA for that product in their country.

Devices:

Directive 93/42/EEC contains the basic legal framework for the regulation of medical devices in the EU, however this has been replaced by the new Medical Devices Regulation 2017/745 (MDR) which comes fully into effect in May 2020. Medical devices (products or equipment intended generally for medical use) are regulated by national competent authorities (HPRA in Ireland). The HPRA has designated NSAI as the NB in Ireland to carry out conformity assessment procedures to ensure compliance with applicable Medical Devices Legislation. Conformity assessments are a service to manufacturers in an area of public interest. Manufacturers are free to choose any NB in the EU that has been legally designated to carry out the conformity assessment procedure.

‘CE’ (Conformité Européenne) markings appear on many products sold in the EU. CE Marking on a product is a manufacturer’s declaration that the product complies with the essential requirements of the relevant European health, safety and environmental protection legislation. CE Markings cannot be affixed to products until all necessary certifications have been obtained from the NB (or depending on the medical device’s class, through a self-certification). Not all products sold in the EU require CE marking, however it is mandatory for medical devices, in vitro medical devices and active implantable medical devices.

Certain persons who intend on placing medical devices on the market must register their contact details and details of their devices with the HPRA.

The three main EU Directives regulating the marketing and safety of medical devices placed on the market were:

1. Directive 90/385/EEC concerning Active Implantable Medical Devices (AIMDD)
2. Directive 93/42/EEC concerning General Medical Devices (MDD)
3. Directive 98/79/EC concerning in-Vitro Diagnostic Medical Devices (IVDD)

These Directives and the related Irish Regulations require manufacturers, nominated Authorised Representatives or anyone seeking to place medical devices on the EU market to provide information to the HPRA (relevant competent authority).

Regulation 2017/745 on medical devices and Regulation 2017/746 on in vitro diagnostic devices entered into force on 25 May 2017 and will take effect in May 2020 and May 2022 respectively. These Regulations replace the above listed Directives to be transposed into national legislation.

2. Pricing & Reimbursement

In Ireland, in order to decide which medicines or medical devices will be reimbursed under the social security system, the HSE (like all other EU competent national authorities) has the independence to set the prices of medicinal products and medical devices (non – drug products).

The HSE has statutory responsibility for medicine and non – drug (medical device) pricing and reimbursement under the Health (Pricing and Supply of Medical Goods) Act 2013. Their website provides guidelines and lists for reimbursable items including medicines and aids (Reimbursement List).

There is a standard application procedure (other than for cancer drugs) to have products included on this list via which suppliers can make reimbursement applications to the HSE. Ireland does not have a distinct approval procedure for reimbursements for rare disease medicines or hi – tech products.

The 2013 Act outlines the criteria for decisions regarding the reimbursement of medicines and non – drug products (medical devices). The decisions made by the HSE are made objectively, and they are advised by the National Centre for Pharmaeconomics (NCPE) which makes recommendations as to which medicines are to be reimbursed by the taxpayer. Where a company fails to demonstrate the clinical benefit to support the price it is seeking for its product, the HSE can decide to not make a reimbursement.

The Medicinal Products (Control of Placing on the Market) Regulations 2007 (SI 540/2007) outlines the requisite criteria for establishing the legal sup- ply status of medicinal products. The two main categories of medicinal products are prescription – only and non – prescription products. New medicines generally may only be supplied on prescription; however when/if the medicine has a well-known, long established safety profile and there is evidence that the medicinal product may be safely used without supervision by a physician, an application can be made for reclassification from prescription-only medicine to pharmacy-only status.

Generally, the Irish State will only reimburse prescription – only products, however non – prescription items, such as generally available painkillers, can be reimbursable where prescribed by a doctor. The State operates four principal reimbursement schemes to determine whether people free or subsidised medicines. These schemes are as follows:

1. General Medical Services Scheme: this is a means – tested scheme and patients pay €2.00 per item prescription and this goes up to a maximum of €20 per family per month. Pharmacists obtain dispensing fees but no mark – up fees.
2. Long Term Illness Scheme: this is not means tested and applies to specific long-term conditions such as epilepsy and diabetes. Patients pay a maximum of €124 per month and pharmacists receives a mark – up and dispensing fee.
3. Hi – Tech Scheme: patients receive expensive medicines required for long – term care and, if they hold a medical card or the medicine is a specific condition under the Long Term Illness Scheme they receive the medicine free of charge. Alternatively, they pay the first €124 a month as per the Drug Payment Scheme.
4. Drug Payment Scheme: patients pay a maximum of €124 per month and pharmacists receives a mark – up and dispensing fee

In 2016 the Irish State entered into a framework agreement with the Irish Pharmaceutical Healthcare Association (IPHA) for the supply and pricing of medicines in an attempt to reduce healthcare expenditure. The 2016 IPHA Agreement involves the Department of Health in reviewing products that cannot be funded within HSE resources. The product is reviewed by the HSE, and if they cannot reimburse it, they can inform the Department of Health who can apply to the government to consider providing funding for the product. The methodology for reimbursement of drugs consists of ex-factory prices (price to wholesaler) and wholesale mark – up price.

Where a supplier is not seeking reimbursement, they do not need to agree a price for a medicinal product prior to placing it on the Irish market. The 2013 Act provides for introduction by the HSE of a system for reference pricing of medicines that are deemed as interchangeable; this will allow a common reimbursement price for these medicines. This Act specifically excludes biologics from being considered as interchangeable.

The EU Transparency Directive (Council Directive 89/105/EEC) aims to allow for transparency across the Union in respect of the pricing and reimbursement of medicinal products. It does not affect national policies or social security systems, except, as is required to achieve transparency.

3. What are the steps to obtaining authorization to develop, test, and market a product?

In Ireland, authorisations to market new medicinal products are granted by the HPRA under the Medicinal Products (control of placing on the market) Regulations 2007. An Irish authorisation for a human medicinal product is called a product authorisation (PA). Details on the content of an application are outlined in EU Directives 2003/63/EEC.

4. What are the approximate fees for each authorization?

The HPRA’s website provides a spread sheet listing numerous fees for varying applications and some of these are as follows:

• Authorisation of medicines (new National Application) – €20,000
• Authorisation of medicines (new Mutual Recognition Concerned Member State Application) – €14,000
• Authorisation of medicines (new Mutual Recognition Reference Member State Application) – €15,000
• Authorisation of Medicines (new Decentralised Concerned Member State Application) – €20,000
• Authorisation of Medicines (new Decentralised Reference Member State Application) – €50,000

There are further details on fees for applications for the Maintenance of Authorisations or Registrations, Enforcement Fees, Homeopathic Product Registration and Authorisation as well as for Renewals and Transfer of Ownership (amongst others).

5. For how long are marketing authorizations/registrations valid? How are marketing authorizations/registrations renewed?

Marketing authorisations are valid for a period of five years from the date of issue. In order for MAs to remain valid, renewal applications must be made to the HPRA at least nine months before expiry of the original authorisation. Following renewal, the authorisation remains valid for an indefinite period unless, on drug safety grounds, the HPRA decides to mandate one additional five – year renewal.

For products authorised by the European commission (centralised procedure) renewal applications must be submitted to the European Medicines Agency (EMA).

6. How does the authorization process differ between brand- name products and generic products? Are there differences for local manufacturers versus foreign-owned manufacturers?

Brand – name & Generic Products:

Depending on the data submitted in an application for authorisation, medicines are classified into two main types, reference and generic (interchangeable) medicines. The data requirements for these are harmonised in law across the European Community and the definitions of these medicines are outlined in EU legislation (Directive 2001/83/EC).

A reference medicine is one that has been authorised following the submission of a dossier containing full pharmaceutical, pre-clinical and clinical trial data. These medicines are also called branded, originator or proprietary medicines. Following authorisation, they are entitled to a ten-year period of market protection prior to the introduction of a generic medicine.

A generic medicine contains the same quantity of active substance and is used in the same dose to treat the same condition as a reference medicine. It must meet the same standards of quality and safety and have the same effect as a reference medicine. However, the data submitted for authorisation of a generic medicine is reduced and there is scope for applicants to omit some or all of the preclinical and clinical data. The dossier for a generic application must contain full pharmaceutical data and the clinical data may include a study demonstrating bioequivalence with the reference product, however in certain circumstances a waiver of bioequivalence can be submitted.

The requirements for bioequivalence data are harmonised across the EU. A bioequivalence study is performed in healthy volunteers who receive single doses of the reference and generic medicine and blood samples are taken to determine the handling of the medicines by the body. The reference and generic medicines are considered “bioequivalent” when they produce the same plasma concentration of active substance in the body when tested. When a generic medicine is demonstrated to be bioequivalent to a reference medicine, the benefits and risks of both medicines are considered the same and the generic medicine can usually be substituted for the reference medicine. Where bioequivalence cannot be demonstrated, bridging data is required to demonstrate that the differences do not affect the product’s safety and effectiveness.

Local Manufacturers versus Foreign – Owned Manufacturers:

As discussed in Question 2, there are four methods of obtaining an MA and these are as follows:

• Centralised Application Process
• National Procedure
• Mutual Recognition Procedure
• Decentralised Procedure

If local manufacturers only wish to put their products on the Irish market, they can use the National Procedure. The other three methods can be used by both local manufacturers and foreign – owned manufacturers in order that their products can be offered throughout the EU.

7. How are combination products (drug + drug, drug + biologic, drug + device, biologic + device, drug + biologic + device) regulated?

As per the EMA’s guidelines, medicines can be marketed for use in combination with a medical device, usually to enable the delivery of the medicine. If the principal intended action of the combination product is achieved by the medicine component, the entire product will therefore be regulated as a medicinal product under Directive 2001/83/EC or Regulation (EC) No 726/2004. The two types of combination product are as follows:

1. Integral – medicinal product and the device form a single integrated product for example single dose pre-filled syringes, pens and injectors and;
2. Co-packaged – the medicinal product and the device are separate items contained in the same pack. For example an injection pack which has separate needles and filter needles.

Article 117 of the Medical Device Regulation (MDR) (EU 2017/745) amends the existing Directive on Medicinal Products for Human Use (2001/83/EC) by introducing a new requirement for medicines with an integral device. The MA application should include either a CE Marking or a declaration of conformity for the device. If the device is not CE marked but needs to be certified as it will be marketed separately, then the applicant must also include an opinion from a notified body on the conformity of the device.

In June 2019 the EMA released guidelines for public consultation on quality requirement for submissions for drug – device combinations. Stakeholders were invited to send their comments by 31 August 2019. The EMA will take these comments into account with a view to finalising the guidelines prior to full application of the Regulation in May 2020.

8. How is compliance with regulations monitored and evaluated? Is the regulatory regime comparable with the U.S. Food and Drug Administration or the European Medicines Agency expectations and requirements?

In Ireland, compliance with regulation is monitored and evaluated by the HPRA in accordance with EU legislation and regulations which includes EMA expectations and requirements. HPRA as the national competent authority has the requisite authority for oversight of regulation of the pharmaceutical industry. They regularly inspect manufacturers of medicines in order to ensure compliance with Good Manufacturing Practice standards.

9. What is the potential range of penalties for noncompliance?

Medicines:

The Irish Medicines Board Act 1995 (as amended, 1955 Act), provides for the HPRA (formally known as the Irish Medicines Board) to appoint authorised officers and gives a wide range of investigatory powers that may be exercised in the course of an investigation, inspection or any other function undertaken under the 1995 Act or any other Regulations made under the Act.

Section 32 of the 1995 Act also confers extensive powers on the Minister for Health to make regulations for the purposes of the Act. Section 32(4) of the Act makes it an offence to contravene any regulation made under Section 32. The HPRA can bring summary proceedings for an offence under the 1995 Act; the time limit for prosecution is two years from the date of the offence. In cases of more serious offences where summary proceedings are not appropriate, trial will be on indictment by direction of the Director of Public Prosecutions in the Criminal Court and the penalties for conviction are:

• First offence: a fine not exceeding €120,000 or imprisonment for a term not exceeding ten years or both
• Subsequent offence(s): a fine not exceeding €300,000 or imprisonment for a term not exceeding ten years or both

If an offence is committed by a body corporate with the consent, connivance or by the negligence of a director, manager or other officer if the body corporate, that person may be personally liable. The HPRA carry out investigations relating to illegal supply, manufacture or advertising of health products and they prosecute where they have detected a significant risk to public health or where compliance cannot be achieved or if there are other aggravating factors. They liaise with other national agencies including the police and Customs as well as with their international counterparts.

The IPHA has a self-regulatory code, and if signatories breach the Code of Practice for the Pharmaceutical Industry (Pharmaceutical Code), the IPHA Council can opt for a range of penalties including (but not limited to), reprimanding the company for breach of the Pharmaceutical Code, ask the company to cease the practice which brought them into breach and recommend to the IPHA Board of Directors that the company be suspended or expelled from the IPHA. They may also opt to charge administrative fees, and their findings are published annually and made available to IPHA members as well as the HPRA and the Minister for Health.

Devices:

The HPRA’s compliance programme is to ensure that medical devices legislation is complied with. Compliance is conducted in a number of ways including review of technical documentation, random sampling examination and testing, and auditing of manufacturing facilities or authorised representatives. If a HPRA Authorised Officer has reasonable grounds to suspect that there has been an offence under the medical device legislation, they can seek a search warrant to inspect the relevant premises. If an offence is committed by a body corporate with the consent, connivance or by the negligence of a director, manager or other officer if the body corporate, that person may be personally liable. Any person or body corporate found guilty of an offence will be liable on summary conviction and can be subject to six months imprisonment, a fine, or both.

There are also penalties under the Irish Medtech Code, which, as per the IPHA, is a self-regulatory body. The Irish Medtech Association can decide to issue a formal letter of reprimand, issue a letter of reprimand and recommend suspension of the company from the Irish Medtech Association (with various conditions) or recommend expulsion from the Irish Medtech Association.

10. Is there a national healthcare system? If so, how is it administered and funded?

In Ireland, national healthcare policy and expenditure is determined by the Department of Health under the guidance of the Minister for Health and is funded by an annual government budget. Public healthcare services are provided by the HSE which owns and runs public hospitals. The HSE was established under the Health Act 2004 as the single body with statutory responsibility for management and delivery of health and personal social services in Ireland. Every resident in Ireland is entitled to subsidised or free approved prescribed medicines as well as certain medical aids and appliances.

11. How does the government (or public) healthcare system function with private sector healthcare?

The Irish healthcare system is two tiered, comprising of the public healthcare service which is administered by the HSE, and the private healthcare system which is funded by private funds and private insurance. There are also voluntary public hospitals and the majority of their income comes from State funds. They are sometimes owned by private bodies such as religious orders. In practice, public hospitals and public voluntary hospitals are not different and most of them offer private healthcare, but there is a clear distinction between public and private beds. There is a set daily charge for private patients in public hospitals.

Private hospitals operate purely independently of state health service, and patients who opt to go private must pay (or their insurance company must pay) for the full cost of their treatment and maintenance. Private hospitals are free to set their charges to their patients at rates of their own choice. As of the end of 2018, almost half of the Irish population hold private health insurance and can avoid the potential for lengthy waiting lists associated with public health services.

12. Are prices of drugs and devices regulated and, if so, how?

As outlined in Question 2 above, the prices of drugs and devices are considered by the HSE in line with Health (Supply and Pricing of Medical Goods) Act 2013 where manufacturers (or others in the supply chain) are seeking reimbursement. Where reimbursement is not being sought, a price does not need to be agreed by the HSE for a medicine or medical device prior to it being placed on the Irish market.

13. How are the drugs and devices used by patients paid for? What roles do public and private payers play?

If you are ordinarily resident in Ireland, then you may be eligible for free or subsidised prescribed drugs and medicines as well as certain medical and surgical aids and appliances. As outlined in Question 2, there are four principal means-tested reimbursement schemes run by the State under which patients can receive free or subsidised drugs, medicines and aids and appliances. The HSE Primary Care Reimbursement Scheme provides the Reimbursement List of medicines or aids provided under a Medical Card or HSE schemes.

Medical card holders who are prescribed items that are not on the list can apply for a discretionary hardship scheme. Furthermore, if you have a Medical Card, the HSE will pay the reference price for an interchangeable medicine. However if you wish to choose a more expensive medicine, you must pay the difference between the reference price and the retail price. Medical aids and appliances are usually free to medical card holders and those who do not have a medical card often get their aids for free if the aids are required as part of hospital treatment. If someone does not hold a Medical Card, they can apply to their local health board for a contribution towards the price. Furthermore, health insurers will also often refund part of the cost of surgical or medical aids.

14. Who dispenses drugs and devices to patients and how are those dispensers compensated?

1. Medicines – drugs dispensed in the community are funded by the State through reimbursements of pharmacists where patients are covered by a reimbursement scheme and where the product being dispensed is on the Reimbursement List. Payments are regulated by S.I. No. 279/2013 – Health Professionals (Reduction of Payments to Community Pharmacy Contractors) Regulations 2013 and HSE Community Pharmacy Contractor Agreements. In general, all pharmacies have agreements with the HSE under the Primary Care Reimbursement Services Scheme to dispense approved drugs and medicines. General Practitioners (GPs) can also provide drugs and medicines directly to patients in circumstances where there is only one practice centre which is three or more miles from a retail pharmacy.
2. Devices – the HSE reimburses medical devices (that are on the Reimbursement List) via their Aids and Appliances Schemes. Hospitals and other specialist institutions provide the aids and appliances (as well as drugs and medicines) directly to patients.

15. What are the professional and legal responsibilities of those who dispense drugs and devices? What role do they play in providing patient care, information, and safety?

Medical practitioners in Ireland must adhere to the Medical Council’s Guide to Professional Conduct and Ethics for Registered Medical Practitioners and pharmacists are obliged to adhere to the Pharmaceutical Society of Ireland’s Code of Conduct (PSI). Medical practitioners and pharmacists commit themselves to abiding by and adhering to the ethical guidelines and professional standards set by their regulator.

Both the Guide and Code of Conduct require compliance by medical practitioners and pharmacists with medicines legislation, which includes controlled drugs. The movement and supply of controlled drugs is legislated for under the Misuse of Drugs Acts and Regulations in Ireland, more specifically the Misuse of Drugs Regulations 2017. These are necessary in protecting patient health and safety, and it is an offence not to adhere to these regulations. It is incumbent upon medical practitioners and pharmacists to be aware of their obligations under the legislation to ensure safe supply and appropriate dosage to their patients and ensure patient safety.

The PSI and the Medical Council have issued joint guidance in regards to safe prescribing and dispensing of medicines and drugs. The joint guidance lists the following as their respective obligations:

Prescriber Obligations:

• Provide a valid prescription which meets the requirements of the legislation
• Be satisfied as to the identity of the person for whose treatment the prescription is to be issued
• Follow relevant national and international prescribing guidelines
• Within reason, be available to confirm or discuss any matters related to the prescription and the patient
• Ensure the safe keeping of prescription pads to reduce the risk of theft and forgery
• Facilitate appropriate withdrawal of controlled drugs and follow-up and refer as necessary

Pharmacist Obligations:

• Only dispense on the basis of a legally valid prescription
• Be satisfied that the signature of the prescriber is genuine
• Prior to supply, be satisfied as to the identity of the person or bona fide representative presenting the prescription or collecting controlled drugs
• Be vigilant for forgeries or unusual prescribing pattern
• Store controlled drugs in a safe manner, in accordance with the relevant legislation
• Record all supplies of schedule 2 controlled drugs (Misuse of Drugs Regulations 2017) in the pharmacy’s controlled drugs register
• Communicate with the medical practitioner if there is any query about the prescription or care of the patient
• Adhere to national guidelines and facilitate appropriate withdrawal of controlled drugs and follow-up and refer as necessary