II.2	EU Regulatory Frameworks for Medicines and Medical Devices for Cardiovascular Disease

A. Introduction

The European system for regulating the manufacturing and distribution of medicinal products developed following the thalidomide disaster in the early 1960s. Unprecedented advances in science, pharmacology and therapeutics have been discovered in the past few years. Dramatic changes have taken place in the methods in which the pharmaceutical industry discovers and develops new products. These advances were followed by methodologies to evaluate the safety and efficacy. The goal is to identify the appropriate benefit:risk ratio of new products before placing each product safely on the market. It is recognized that to fully meet the needs of public health in ensuring the objective evaluation benefit risk ratio of new medicines combined with medical devices as delivery systems changes will need to be made. This is particularly exemplified in the regulatory assessment of the safety of new cardiovascular therapeutics.

This article describes the key elements of the current European legislative frameworks for medicinal products and medical devices and how these frameworks are applied to new cardiovascular therapies. In particular the co-development of medicines based on what are now defined as advanced medicinal therapies and medical devices are becoming increasingly important.

We will review the clinical developments of anti-thrombotic compounds in combined medical device/medicinal products of drug eluting stents and other developments of advanced medicinal therapies in cardiology to highlight the intrinsic difficulties with regulation of such products.

B. Medicinal products

The principal European legislation is Directive 2001/83/EC as amended by Directive 2004/74/EC. This stipulates all the requirements for the contents of the application dossier and grant of marketing authorization of medicinal products. In particular the Directive and its associated notes for guidance specify the non-clinical pharmacology, toxicology and clinical safety and efficacy data needed to evaluate the appropriate benefit risk profile of a new medicinal product.

The European Medicines Agency (EMA) is responsible for coordinating all applications for marketing authorization within the European Union (EU). The Agency’s administrative secretariat coordinates the scientific, technical and medical assessments by appropriate experts in the Member States and producers can choose between several procedures, all of which allow for harmonization of authorization throughout the EU.

The scope and powers of the European Directive are set by the definition of a medicinal product: ‘any substance or combination of substances presented as having properties for treating or preventing disease in human beings’.

Also the scope and operation of the administrative system for mutual recognition and centralized assessment have been expanded and accelerated. Conditional authorization and advice on the compassionate use of new unauthorized medicines have also been introduced.

Besides the Medicines Directive’s major objective of protecting public health it also has the parallel responsibility of encouraging innovation by the pharmaceutical industry. This is achieved by introducing periods of data and marketing exclusivity into marketing authorizations before data on their risk benefit can used by generic copy products, the designation of certain products designated for the treatment of ‘orphan’ diseases and those for pediatric treatment. In general, data exclusivity has been harmonized to ten years plus one extra year for important new therapeutic indications. There has also been substantial reinforcement of the European systems for “pharmacovigilance” and risk management.

A further incentive for innovation is the extension afforded to the patent protection of individual products (not the active ingredients) by the national grant of supplementary patent certificates (‘SPC’) for significant new indications.

There are two types of authorization – national (for marketing in a single Member State) and centralized (for marketing throughout the entire European Community) together with a number of different procedures for obtaining such a marketing authorization (1).

The centralized procedure is mandatory for products for the treatment of AIDS, cancer, neurodegenerative disorder or diabetes and is optional for any other products containing new active substances not authorised in the Community before 20 May 2004 or for products which constitute a significant therapeutic, scientific or technical innovation or for which a Community authorization is in the interests of patients or animal health at Community level.

The decentralized procedure is an application for national authorization in more than one Member State at the same time under Article 28(1) and (3) of the Directive.

There is also the purely national procedure in accordance with Articles 8 and 10 of the Directive provided the product has yet to be authorized in another Member State. The company may then obtain authorization in other Member States under mutual recognition.

Under the Mutual recognition and decentralized procedures a person holding marketing authorization in one or more member States applies for mutual recognition of the authorization granted in the original member state (2). The decentralized procedure (DCP) applies where a product has not been authorized in the European Economic Area and the applicant wishes to apply simultaneously in more than one member state. The procedures are almost identical apart from the DCP being a completely new assessment. Any disagreement between Member States is referred to the Coordination Group on Mutual Recognition and Decentralized Procedures. If no agreement is reached the matter is referred to the Committee on Medical Products for Human Use (CHMP). The Committee produces an opinion and the Commission adopts a decision, which is binding on Member States.

An applicant cannot avoid the mutual recognition of DCPs following the grant of a centralized marketing authorization (3). In addition to assessing the safety and efficacy data and benefit risk profile the competent authority must assess the product’s labeling and package leaflet to ensure compliance with the Directive’s requirements.

C. Medical Devices

In contrast with the regulatory regime for medicinal products, the manufacturers of medical devices do not have to submit pre-marketing data on safety and efficacy and risk: benefit evaluation for assessment by a national medicines regulatory agency for grant of marketing authorization. The manufacturer only has the duty to ensure that the product complies with the relevant legal essential requirements (see below), subject to an independent technical organization, a ‘notified body’, approval.

The manufacturer must perform an appropriate conformity assessment and certify compliance with the relevant essential requirements in a declaration of conformity (Directive 93/42/EEC). There is usually a choice of conformity assessment procedures open to the manufacturer depending on the risk-based classification under which the device is categorized. The two main procedures for conformity assessment are either an approved total quality assessment procedure audited to ISO 9000 series standard, as customized for medical devices with EN 46000 series standard, or individual product assessment.

The essential requirements relate to the safety in use of the device, including labeling requirements. They are expressed as scientific and technical performance characteristics and efficacy, and thus risk:benefit assessment is not a specific requirement.

Confirmation of conformity must include evaluation of clinical data either from bibliography or clinical investigations. Conformity with essential requirements is attested by the fixing of a European CE (define) mark, which effectively acts as a passport allowing the device to be placed on the market and to circulate freely within the European Economic Area.

Manufacturers of medical devices also have post-marketing surveillance and vigilance requirements. In parallel, Member States have market surveillance obligations and if a medical device is subsequently found to be unsafe after being placed on the market, the National Competent Authority has power under a safeguard clause to order withdrawal of the product in its jurisdiction. At this juncture, the issue may be referred to the Commission.

D. Current European Legislation

• Three Directives regulate medical devices. They all adopt the ‘new approach’ scheme for product regulation, which includes many other product sectors.
• The Medical Devices Directive (93/42/EEC): covers a wide range of devices from first aid bandages to hip prostheses.
• Active Implantable Medical Devices Directive (90/385/EEC): covers all powered implants or partial implants, which are left in the human body, such as cardiac pacemakers.
• In vitro Diagnostic Medical Devices Directive (98/79/EC).

E. National Competent Authorities and Notified Bodies

Each Member State has designated a governmental authority responsible for implementing the Devices Directives within its jurisdiction. In the United Kingdom, the principal function of the Medicine and Healthcare Products Regulatory Agency (MHRA) is to ensure safety and health of patients and users of medical devices. The MHRA is not involved in assessment or authorization for placing on the market. This is the responsibility of a third party testing house, the notified body. This is a private commercial enterprise approved by the Competent Authority in their Member state. Notified bodies are approved for the purposes of the legislation by the competent authority and are then notified within the Community by the publication of their approval in the Official Journal. Notified bodies may be approved for all devices or only for specific classes of devices and can be approved for all devices or only for specific classes. The Manufacturer can choose any notified body and has a contractual relationship with it. Medical devices are classified into four categories according to degree of risk (see Table 1). There are three basic criteria for the categorization of risk: duration of contact with the body, degree of invasiveness and anatomy affected by the device.

Manufacturers have a have an obligation to report adverse events to national competent authorities and member states have to report and evaluate ‘any malfunction or deterioration in the characteristics and performance of a device, or inadequacy in the labeling which might lead to or have led to the death of a patient or user or to a serious deterioration in his state of health’. Manufacturers also have post-marketing obligations under ‘new approach’ or medical devices legislation and/or General Product Safety legislation and under product liability and/or negligence law. As an example the Medical and Healthcare products Regulatory Agency (MHRA) has issued guidance on the corrective action, e.g. the return, modification, exchange, destruction or retrofit of a device. This guidance also covers in general terms in which a recall might be appropriate and how it should best be implemented.

Generic market surveillance and post-marketing requirements apply to all new approach products. Surveillance and post-marketing obligations apply to manufacturers, importers and distributors for all medical devices (4).

There are two types of enforcement provisions: investigative powers (Relevant product specific regulations and Part II CPA 1987) and indictable offences.

F. Advanced Therapy Medicinal Products (ATMP)

The category of products designated in the Directive as ‘Advanced therapy medicinal products’ (ATMP) is particularly important in the development of new innovative treatments for cardiovascular disease (5,6).

Many advanced therapy products for use in cardiology are combinations of medicinal product and medical devices. These products are defined as an ATMP and are regulated as medicinal products, if they fulfill the following conditions (See Table 2):

Combined ATMPs will be evaluated by the European Medical Agency (EMA). The application for a marketing authorisation for a combined ATMP which contains a medical device should include evidence that the device meets the essential requirements laid down in the medical devices legislation and where available the results of an assessment by a notified body in accordance with the medical devices legislation. If the application does not include the results of a notified body’s assessment, the EMA will seek a notified body’s assessment unless the Committee for Advanced Therapies, advised by its experts for medical devices, decides that the involvement of a notified body is not required.

When considering the risk:benefit balance the authority must consider all risks relating to quality, or safety or efficacy of the product as regards patient’s health but not risk to the environment. Consideration of benefit:risk must also take into account the ‘precautionary principle (7). Grant of Marketing Authorization is refused if any of the criteria in Table 3 are not met.

G. Proposed Changes and Implications for Devices in Combination with Advanced Therapy Medicinal Products (ATMPs)

Following the safety issues with PIP breast implants and metal hip prostheses over the past few years there is now considerable concern as to the effectiveness of the current system of medical device regulation, particularly as regards the lack of a central system monitoring ongoing safety of devices and delays in identifying safety signals and taking urgent remedial action. The European Commission has proposed a new Regulation to address these concerns. The primary objectives of the new regulation will be to improve: the inconsistent performance of Notified Bodies. These inconsistencies include: i) insufficient clinical evidence relating to the safety and performance of a device before it is placed on the market, and ii) imprecise and variable post-market surveillance by manufacturers. The ability to trace devices to improve vigilance and post-market surveillance as well as improve coordination and transparency would be welcomed.

The European Commission has now adopted two proposals for regulation on medical devices and one on in vitro diagnostic medical devices (8).

While this legislation will go some way towards synchronising and coordinating the regulation of combined medicine/medical device products, particularly those categorised as ATMPs, the new regulations do not clearly address the overriding need for prospective safety monitoring vigilance of adverse events as is a routine requirement for pharmacovigilance of products governed by the Medicine Directive.

H. Regulatory Guidance on Stents

Coronary artery stents have become the medical device of choice for the treatment of coronary artery disease. Since their introduction in 1987, significant developments have occurred in stent technology. A major objective of these developments was the reduction of in-stent restenosis, the formation of neointimal tissue inside the stent triggered by vessel injury and the inflammatory response, which results in renarrowing of the coronary artery. Improvements in strut configuration, thickness, and materials have enhanced deliverability and reduced vessel damage. Currently available drug-eluting stents release drugs that reduce neointimal formation through the arrest of cell proliferation. Drug-eluting stents have significantly reduced rates of in-stent restenosis. However, concerns have been raised with respect to their long-term safety, particularly in relation to the occurrence of late thrombosis (9).

The authors have identified the long term safety events with combined medical device/medicinal products as of particular concern and in this writers view the ability to robustly identify these events is a significant weakness of the new device legislation.

Innovative developments particularly products for the regeneration of ischemic damaged tissue will pose significant regulatory and practical problems with respect to ongoing monitoring of benefit:risk, particularly with respect to post marketing safety pharmacovigilance. This is a complex task compounded by rapid dissemination of new medical technology, lack of standards in data collection, current lack of unique device identifier information and inadequate adverse event reporting mechanisms. Much work is now being done to experiment with new distributed medical device safety surveillance systems.

For example Vidi et al at Harvard have developed a new automated computerized tool, DELTA (Data extraction and longitudinal trend analysis system) (10). This system is designed to prospectively monitor the adverse event rates of new medical products, both for medicinal products and devices through continuous surveillance of existing clinical databases and registries used in patients undergoing percutaneous coronary interventions (PCI). Vidi et al tested the system on a large clinical data base as well as randomized clinical trial data to evaluate adverse event rates of several drug-eluting stents, vascular devices and embolic protection devices (10). The study specifically compared time savings between the DELTA system classes of new cardiovascular therapeutics (network detection of true device safety alert) and the time taken to detect the same outcome using currently available conventional retrospective safety monitoring. It also evaluated the sensitivity specificity, positive predictive value and negative predictive value of the DELTA system network.

This pilot study in five centers in Massachusetts evaluated those attributes that will be required to efficiently perform prospective safety surveillance of combined medical device and medicinal products for the ongoing evaluation of benefit risk.

Another example is the quick pace of the development of cell therapies for heart failure based on stem cells of skeletal myoblasts (11). Although many important issues (eg, mechanism(s) of action of stem cells, long-term engraftment, optimal cell type(s), dose, route, and frequency of cell administration) remain to be resolved, and cell therapy has not been conclusively shown to be effective, it is likely that well-designed trials and pre-clinical studies will resolve these issues. One way in which such difficulties may be overcome will be the introduction of a new regulatory paradigm, ‘Adaptive Licensing’.

I. Discussion and Conclusions

This type of system will become especially important if and when newer regulatory frameworks are introduced to allow foreshortened regulatory timelines and earlier access to the market place for significantly improved innovative products.

The concept of adaptive licensing (AL) has been defined by the EMA as the ‘staggered approval’ of new medicinal products, which would not be covered by conditional marketing authorizations (12). AL is a prospectively planned adaptive approach to the regulation of drugs, through iterative phases of evidence gathered by regulatory evaluation and license adaptation. The concept seeks to maximize the positive impact of new drugs on public health by balancing the timely (potentially earlier) access for patients with the need to provide adequate and appropriate evolving information on benefits and risks. As currently envisaged by the EMA, the process would build on existing regulatory procedures including conditional authorization and pharmacovigilance tools for monitoring drug safety.

The key issues in the introduction of AL procedures would be: increasing the dependence on pre-clinical toxicology and pharmacodynamic data as predictors of safety and efficacy in the clinical setting; reducing the quantity of clinical trial data in man and patients for the robust evaluation of benefit risk; the adequacy of warnings and contraindications in the labeling and packaging of AL early access medicines.

In conclusion the breadth and depth of these innovative therapeutic technologies ranging from stem cell regeneration of damaged cardiac tissue to new and complex in situ drug delivery systems for long term anti-thrombotic therapy highlight the need for a regulatory framework that is able to deal with these issues of defining appropriate benefit risk profiles in as efficient and timely way without the complexity and difficulties currently inevitable in the current European framework. These advanced therapies demand a new paradigm such as adaptive licensing which could safely lead to earlier access to marketing authorisation and earlier patient use.

 

References

1. Anonymous Title III of Directive 2001/83/EC and Title II of Regulation (EC) No 726/2004., EC Title III of Directive 2001/83/EC Title II of Regulation EC
2. Anonymous (2012) The Medicines for Human Use Regulations.
3. Anonymous (2001) Title III of Directive 2001/83/EC Title II of Regulation EC
4. Anonymous (2008) Decision European Community.
5. Anonymous (2001) A gene therapy medicinal product as defined in Part IV of Annex 1 to Directive 2001/83/EC A somatic cell therapy medicinal product as defined in Part IV of Annex 1 to Directive 2001/83/EC.
6. Anonymous (2007) A tissue engineered product as defined in Article 2 1 (b) of the ATMP Regulation (Regulation EC) No 1394/2007, Regulation EC No1394.
7. Communities CotE (2000) Communication from the Commision on the precautionary principle.
8. Council EPa (2012) Proposal for a REGULATION OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL on medical devices, and amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009. Regulatary Document (2012/0266 (COD)).
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10. Vidi VD, Matheny ME, Donnelly S, & Resnic FS (2011) An evaluation of a distributed medical device safety surveillance system: the DELTA network study. Contemporary clinical trials 32(3):309-317.
11. Eichler HG, et al. (2012) Adaptive licensing: taking the next step in the evolution of drug approval. Clinical pharmacology and therapeutics 91(3):426-437.
12. Sanganalmath SK & Bolli R (2013) Cell therapy for heart failure: a comprehensive overview of experimental and clinical studies, current challenges, and future directions. Circulation research 113(6):810-834.