The contrast between the United States and European Union is no more apparent than when we consider the approach to centralized oversight of pharma and medical device regulation.

REGULATORY BACKGROUND

In the United States, the US Food and Drug Administration (FDA) provides centralized oversight of pharmaceuticals, medical devices, food and cosmetics. The European Union has no equivalent centralized body. Instead, multiple authorities govern different product categories and jurisdictions:

> The European Medicines Agency (EMA) governs drugs at the EU level.

> National authorities, e.g., the UK Medicines and Healthcare Products Regulatory Agency, Germany’s Federal Institute for Drugs and Medical Devices, and the Spanish Agency of Medicines and Medical Devices, oversee pharmaceuticals and medical devices at the state level but do not authorise medical devices.

> State or regional authorities within EU Member States supervise drug and medical device manufacturing, and inspect manufacturing facilities.

> Notified bodies are private entities assigned to conduct certain regulatory functions, including certifying medical devices. 

EU legal instruments include regulations, which apply directly to EU Member States, and directives, which must be implemented into each Member State’s national law in order to become applicable.

EU APPROVAL PATHWAYS FOR PHARMACEUTICALS

As in the United States, pharmaceutical products generally must undergo clinical trials in order to obtain marketing authorisation, and each clinical trial must receive authorisation before it may commence. EU pre-marketing clinical trials include three phases, each with an increasing number of patients involved.

Unlike the United States, however, there are four different marketing authorisation procedures for drugs in the European Union:

> The national procedure provides marketing authorisation for a drug in a single EU Member State and is conducted solely by that Member State’s national authority.

> To obtain authorisation in more than one Member State, a drug manufacturer may use either the  mutual recognition procedure or the decentralised procedure. If the drug in question has already secured approval in one Member State, the mutual recognition procedure applies. If no marketing authorisation currently exists in any Member State, the decentralised procedure is used. Under both procedures, one Member State is selected that has the function of reporting: the Reporting Member State (RMS). The other Member States where seeking approval are the Concerned Member States (CMS). The RMS conducts an assessment of the drug on behalf of all involved Member States. The CMS can comment and under certain conditions, veto the assessment. If the CMS agree with the assessment of the RMS, the drug receives marketing authorisation in all CMS.

> Finally, the centralised procedure is conducted by the EMA and grants authorisation in all EU Member States. The centralised procedure is mandatory for many innovative drugs, including monoclonal antibodies, advanced therapeutic medicine products, orphan drugs, and drugs for certain severe indications, such as cancer and autoimmune diseases. Applicants also may voluntarily select the centralised procedure for drugs that contain new active ingredients or that represent significant innovation. EU-wide authorisation under the centralised procedure is granted by the European Commission.

EU law offers two paths for expedited drug review and approval: the priority medicines system (PRIME) and conditional approval. To be eligible for PRIME, a drug must demonstrate a major therapeutic advantage or applicability to patients that currently have no treatment alternatives. PRIME-eligible drugs receive accelerated EMA review, i.e., 150 days instead of 210.

Conditional approval is another option for significantly accelerated market entry. Eligible products include drugs indicated for severe diseases, tests to be used in emergency situations and orphan drugs. Applicants for conditional approval must demonstrate that the public benefit of releasing the drug immediately—with incomplete clinical data—outweighs any risk involved in doing so.

Conditional approval may be granted for drugs still in phase I or II clinical trials, and is valid for one year. Upon completion of the clinical trials, including phase III, conditional approval may be converted to standard approval.

RECENT DEVELOPMENTS

The Clinical Trials Regulation (EU) No. 536/2014 (CTR) is expected to enter into force by the end of 2019 upon completion of a new EU clinical trial database. This regulation represents a significant step towards harmonisation and will facilitate multicentre clinical trials in EU Member States. A new EU portal will allow drug manufacturers to submit a single clinical trial application and receive authorisation for all clinical trial sites in the European Union. The CTR also includes strict timing requirements to accelerate the granting of any authorisation.

"The Clinical Trials Regulation is expected to enter into force by the end of 2019"

Another key initiative, the EU-US mutual recognition agreement on good manufacturing practice (GMP) inspections, is slated to be fully implemented by July 2019. Under this agreement, US and EU authorities will recognise facility inspections conducted by one another and no longer separately conduct overseas inspections. The FDA presently recognises GMP inspections conducted in 14 EU Member States. For drug manufacturers, full implementation of the MRA will result in less inspections and thereby save time and money. 

EU APPROVAL PATHWAYS FOR MEDICAL DEVICES

The European Union categorises medical devices into four risk classes:  

> Class I – lowest risk

> Classes IIa and IIb – medium risk

> Class III – highest risk

As in the United States, medical devices with predicates notification may be authorised more easily, without the need for a clinical trial.

The EU authorisation procedure for medical devices diverges significantly from FDA protocols. As noted, no centralised EU authority exists for medical device approvals. Medical device manufacturers instead are responsible for self-certification, which includes preparation of technical documentation and a declaration of conformity.

Manufacturers of risk class I devices may complete the self-certification process independently, but for devices in classes IIa, IIb and III, a notified body must be involved in the conformity assessment procedure. in particular to conduct a review of the manufacturer’s quality management system.

RECENT DEVELOPMENTS

The Medical Device Regulation (EU) 2017/745 (MDR), published in 2017, is slated to become fully applicable in May 2020. It will apply directly in all Member States and aims at further harmonisation and enhanced product safety. For example, the MDR expands the scope of medical device law to include certain cosmetic products, such as non-corrective contact lenses, subcutaneous filling material and liposuction equipment. These products will in future have to meet the same regulatory requirements as medical devices.

Furthermore, the MDR will subject certain categories of products to higher risk classification. This applies, for instance, to software. Many software applications are expected to fall into higher risk categories than they currently do. Such applications include software used for diagnostic and therapeutic decision making and software intended to monitor physiological processes.

Currently, medical device manufacturers often launch products in the European Union before the United States, because the EU approval process is considered simpler than the FDA’s. The MDR may change this, as requirements in the conformity assessment procedure will increase for many products.

THE IMPLICATIONS OF BREXIT FOR APPROVAL PATHWAYS

Fast-approaching Brexit carries significant ramifications for both pharmaceutical and medical device regulatory approvals in the European Union. Negotiations are ongoing, and it is hoped that the final withdrawal agreement will include a transitional period extending the application of EU law through 31 December 2020, as is provided for in the current draft. If no such agreement is reached, however, EU law will cease to apply to the United Kingdom on 30 March 2019.

The regulatory consequences are significant. The EMA has already begun relocating from London to Amsterdam, and it is expected that marketing authorisation for drugs will see severe delays during the period of relocation.

Similarly, many notified bodies for certification of medical devices are currently located in the United Kingdom. Even if some of these bodies relocate to the European Union, they will not have the capacity to perform all of the work that UK bodies currently perform. The MDR will compound this shortage of notified bodies by requiring reassignment and putting more products into higher risk classes that require involvement of a notified body. Medical device manufacturers therefore should consider seeking new certifications as soon as possible. For many products, there is the option of a soft transition: until May 2020, certificates may be issued under the current law (MDD) and remain valid until 2024.