Medical Device Link.

Originally Published MDDI April 2003

REGULATORY OUTLOOK

Barry S. Sall

The European combination-product market is the second largest in the world, preceded by the United States and followed by Japan. It represents 26% of worldwide sales, and is estimated at 41 billion €. The sector itself covers a dynamic, innovative, highly competitive industry, with a global market producing 8000 types of products.

Combination Products in the EU

The European regulatory tradition is built around the perceived differences between pharmaceutical products and medical devices. These are substantive differences, mostly involving the mechanism of action. 

In contrast to pharmaceuticals, medical devices do not achieve their principal intended action in or on the human body by pharmacological, immunological, or metabolic means. Traditionally, medical devices are based on engineering technology—the risks involved and the potential impact on the body are of a different nature. This difference has a number of consequences, particularly on the regulatory environment and the life cycle of products. While toothbrushes, sunglasses, sport and leisure equipment, baby diapers, mouthguards, or breathalyzers are not considered medical devices, condoms, first-aid kits, bandages, contact lenses, and prescription eyeglasses, however, are.

In Europe, placing medical devices on the market is not subject to a formal authorization, as is the case with pharmaceutical products. Devices are classified based on a number of rules described in the Medical Devices Directive, which builds on the concept of a risk-based approach related to the device’s duration of use, invasiveness, and associated hazards. In addition, there are special rules for specific types of devices; e.g., those containing animal tissues, blood bags, and those incorporating a medicinal product (drug or biologic). Class III devices present the highest risks and are subject to the most stringent assessment and third-party certification.

There are three types of medical devices incorporated into combination products:

• Devices for the administration of medicines (e.g., empty single-use syringes and reusable spoons or droppers). These items are regulated by the medical device regulations.

• Devices that combine with a medicinal product to form a single, integral product designed to be used exclusively in the combination—e.g., prefilled syringes. These products are not reusable and are subject to Directive 65/65/EEC in the EU. In addition, the relevant essential requirements of Annex 1 of Medical Devices Directive 93/42/EEC apply to safety- and performance-related features of such devices. This means that the combination is assessed by the drug regulatory authorities, and the device also needs to meet the essential requirements of the Medical Devices Directive. This is usually satisfied by the use of a CE mark.

• Devices incorporating a substance, which, if used separately, may be considered a medicinal product. In addition, the substance (the drug) is liable to act upon the body with action ancillary to that of the device—e.g., a heparin-coated catheter. In this case, the medical device assessment authority (notified body) assesses the combination product, and the drug information is sent by the notified body to a drug regulatory authority for assessment of that specific section. The drug regulatory authority must verify the safety, efficacy, and usefulness of the drug.

On that last point, EU drug authorities have recently noted that they continue to have difficulties with claims and stability data for drugs incorporated into medical devices. Each notified body can decide which drug regulatory authority to use for the assessment of the drug; in practice, however, most use either the MCA in the UK or the Dutch MEB. Evaluation can take nine months or more if the drug is a new active substance. There are also fees levied by the drug authorities for this purpose (in addition to the fees charged by the notified body for assessment of the medical device portion of the combination product). For a known drug, the MCA charges between about US $6000 and $12,000 (if the ‘source’ of the drug is known to the authority), and about $55,000 for a new active substance.

Special Provisions. Special provision is made in the medical device directives to exclude from their scope the following substances: transplants, tissues and cells of human origin, and products incorporating or derived from tissues and cells of human origin. Also excluded are transplants, tissues, and cells of animal origin, unless a device is manufactured using either animal tissue rendered nonviable or nonviable products derived from animal tissue. The use of human tissue is under review, but it now appears likely that such products will fall under a new classification, separate from medical devices.

As with other medical devices, gaining a CE mark for a device-containing combination product means that it can be sold freely anywhere in the European Economic Area (i.e., the 15 EU countries plus Iceland, Liechtenstein, and Norway). 
In general, EU authorization (CE marking) for medical devices is deemed easier to obtain than FDA approval. This is mainly because the European Commission has set up the regulation of medical devices to be a light-touch system concerned mainly with safety; therefore, clinical efficacy requirements, while playing a part, are not necessarily as rigorous as those in the United States. Companies can usually get their medical products on the market faster in Europe than in the United States, although for drug-device combinations, the EU pharmaceutical regulatory bodies will scrutinize the drug portion as thoroughly as FDA would. 

Combinations are regulated almost solely on the manufacturer’s intended claims for the product. For example, a wound-care product containing an antimicrobial can be considered a device if the antimicrobial is there to help prevent excessive odor, but it will be regulated as a pharmaceutical if the claim is to treat or prevent infection. There are other situations where the manufacturer largely determines the classification; for example, bone cements with antimicrobials.

Different combinations are regulated differently according to the European Commission’s classifications. A device that is intended to deliver a medicinal product is itself regulated as a medical device. The medicinal product that the device is intended to administer must, of course, be approved according to the normal procedures for medicinal products. Some examples include drug-delivery pumps, implantable infusion pumps, and nebulizers. Note that in a kit comprising an insulin pen and insulin cartridges, the pen is subjected to device approval but the insulin cartridge is considered a medicinal product.

If the device and medicinal product form a single, integral product that is intended exclusively for single use in the given combination, however, that single product is regulated as a medicinal product. Examples of such products include prefilled syringes, transdermal patches, and various implants, such as plastic beads with antimicrobials for bone infections.

In such cases, the essential requirements of the medical device legislation apply as far as the device-related features of the product are concerned (for example, as in the mechanical safety features of a prefilled syringe). The labeling, however, should comply with the requirements for medicinal products.

Ancillary Devices. Medical devices that include drugs having an ancillary action are regulated similarly. It follows from the definition of a medical device that devices may incorporate substances as an integral part, which, if used separately, may be considered to be a medicinal product. Such products are devices, provided that the action of the medicinal substance is ancillary to that of the device, as reflected in the product claim and as supported by the manufacturer’s scientific data. Examples of such devices include catheters coated with heparin or an antibiotic agent, bone cements containing antimicrobials, and blood bags containing anticoagulant or preservation agents.

Examples of products regulated solely as medical devices include bone cement, dental filling material, and sutures. Others include products regulated as drugs in the United States, such as viscoelastic materials employing mechanical or physical mechanisms of action. Such materials may also act as synovial-fluid replacements where visco-supplementation provides support and lubrication. An example is hyaluronic acid. When the predominant claims are of a pharmacological nature and not primarily related to any viscoelastic characteristics, however, such products are classed as medicinal.

Accessories. Products may also be regulated as accessories to medical devices, and therefore classified as devices. The accessories must be intended for use with a device to achieve that device’s intended purpose, or they must enhance the performance of the device. Examples would include contact-lens-care products (disinfecting, cleaning, rinsing, and hydrating solutions, including those that aid the insertion or wearing of contact lenses without a therapeutic claim), disinfectants specifically intended for use with medical devices (e.g., endoscopes), and skin-barrier powders and pastes, or other skin-care products specifically intended for use with ostomy bags. 

In Europe, some products are regulated solely as drugs, including spermicidal preparations, gases for use in anesthesia and inhalation therapy, and topical disinfectants (antiseptics) for use on patients. Some former devices that are now regulated as drugs in Europe include water for injection, IV fluids and plasma-volume expanders, hemofiltration substitution solutions, antacids, artificial tears, and solutions administered in vivo for organ cooling during surgery.

Clearly there is scope for negotiation for products that fall on the borderline, but the manufacturer has a clear choice in many cases, based on the desired claims for the product.

EU First, FDA Later

Can an EU-first plan finance FDA approval efforts? The answer is yes—although it depends on the product. If the product is regulated as a device and the drug portion can be assessed relatively quickly, then approval can be much quicker than with FDA. Some products FDA would regulate as a drug or biological the EU might deem to be solely a device, in which case CE marking via a notified body is likely to be much faster than FDA drug or biologic approval.

Do EU Decisions Influence FDA? During the review process, FDA will evaluate information from a wide variety of sources, including, in some cases, decisions of other regulatory bodies. FDA is in no way bound by the decision of any other regulatory body; however, the rationale used to reach that decision may be informative for FDA. Other regulatory bodies operate with different definitions of medical devices, pharmaceutical products, and biologics, so the impact of these other decisions is not direct. Both EU and U.S. regulatory bodies are independent bodies that make decisions based on their respective criteria. FDA is particularly sensitive about this, although conditions have improved for cross-regional cooperation in the past few years, partly as a result of the ICH process for drugs. 

There has always been close interaction between FDA and various EU member states, and this remains the case today. In essence, though, FDA views the EU approval process for medical devices as not quite as rigorous as its own. There have been years of discussion on a mutual recognition agreement between the United States and EU for devices, but it has been very slow in coming. If a decision from another regulatory body raises a point that is relevant to FDA concerns, it may be useful for the sponsor to provide such data to FDA. 

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