Lost in Translation?

Combination Products Face Additional Regulatory Hurdles Abroad

John Sullivan and Henrik Elbaek

It’s no secret that the combination medical device market is growing at an impressive rate.

According to reports from BCC Research and Business Communications Co. Inc., the combination market is estimated to grow by 13.6% annually, reaching $11.5 billion in 2010, compared with $5.4 billion in 2004. The number of FDA reviews for these products has increased as well.

A combination product integrates biologics, devices and/or drugs into a combined therapy or treatment. Products can be as simple as an antibiotic-coated bandage or as complex as a drug-coated stent. Another group is engineered biologics such as grown cultures, blood, vaccines and engineered tissues. By nature of their multiple mode-of-action components, combination products come with their own unique set of regulatory challenges.

The complexity and nuances of these therapies led the FDA to create the Office of Combination Products (OCP) in 2002 to oversee the approval process, safety and accountability of combination products. While the OCP does not conduct product review, the FDA recognized the need for a central body that would help to translate new product applications into their component parts to ensure that the appropriate divisions are reviewing respective elements. The path to regulatory approval is only recently becoming clearer in Europe, and strides are being made in Asia.

The differences in current regulation and regulatory body structures require that manufacturers be prepared to follow varying regulatory pathways in different regions. Products in the United States will be managed through the OCP and classified by primary mode of action. However, the product’s components will be reviewed by appropriate centers following respective approval processes addressed later in this article.

In Europe, a combination product is categorized as a medicinal (pharmaceutical) product or device based on how the product is integrated. For example, a syringe is regulated under the medical device directive and a drug administered using the device is regulated under the medicinal products directive. However, if the same syringe is pre-filled, it would be considered a medicinal product, because under European regulations a device and drug that form a single, integrated product are regulated as such. No distinction is made in European regulations for combination products, as has been done with the OCP.

Asia: Focus on Japan

Asia has its own system for regulat-ing combination products. Contrast Japan’s Ministry of Health, Labor, and Welfare (MHLW) with the FDA, and you will see a system that is ripe with challenges for companies seeking approval of combination products. Gaining approval for a standard medical device or drug in Japan is rigorous and can be a frustrating process. Companies also may find that both the healthcare market and medical practitioners can be resistant to change and overly bureaucratic. Consider this example of the lengthy processes required for approval in Japan and elsewhere in Asia: Approval times typically are 12 months for PMA (efficacy plus safety) devices compared to six months in the United States; ap-proval times for 510(k) devices—which relates to efficacy only—take three months in the United States compared to four months in Japan, six months in China and six to eight months in Korea.    

It is not uncommon for a US device manufacturer to have a product line that has been made obsolete by a new product, but which is still on the market in Japan due to the effort, time and expense required to gain approval there. It should be noted that the time required to gain approval is lengthened not only by the process, but also for administrative reasons—the MHLW is perceived to be both understaffed and carrying a backlog of applications. The impact of these delays and lengthy processes is that new products offering better patient care are not being marketed as quickly as possible.

The device industry, as a result, incurs more costs associated with managing the review process and with maintaining product lines that are considered obsolete in other markets. The impact can be felt even at the manufacturing efficiency level, if the product introduces new technologies that reduce manufacturing costs. In this scenario, both the American-based industry and the Japanese consumer are losing.

The Japanese regulatory process was revised in 2005 to accommodate combination products, biologics and medical devices, and to allow third-party review for approval. This process is in line with changes implemented at the FDA and in the European Union. However, these processes and systems are still new and will require a period of adjustment. Ultimately, these regulatory improvements will lead to a more efficient approval process but will require that manufacturers remain patient while longstanding practices are supplanted by new review methods.

The View From Europe

In contrast with Japan, regulation is a much more efficient process in the European Union. However, just a few years ago it still was a challenge. Different EU member countries had varying requirements for new product approval.    

In Europe, the Medical Device Directive (MDD) regulations provide guidance for gaining marketing ap-proval through the declaration of conformance process. Ultimately, achieving the right to bear the CE mark designates a device as marketable in Europe. The extent of the requirements for CE marking depends on the product’s classification.

To some degree, CE marking works on the honor system with non-combination, Class I products. All large European companies can actually CE mark themselves. For a new entrant in the market and for certain classifications of product, manufacturers are required to work with notified bodies, which perform third-party certifications of quality assurance systems and products. The FDA and MDD regulations are similar, but American companies face additional work to develop documentation that is not necessarily required by the FDA when it comes to CE marking.

Under EU regulations, one country cannot have more restrictive regulations without a special dispensation. A country with strict rules cannot enforce them if the other countries have more liberal rules. If a country tries to do so without being approved by the European Union, it will be perceived as a trade barrier and the companies actually can sue that country in the EU court. Nevertheless, while European countries have a common set of rules, they each have their own authorities to handle approval of combination products, and they operate on different timetables. A combination product typically will have an unpredictable road ahead for regulatory approval in each EU country.

Moving Forward

As US-based companies develop new combination products that present marketing opportunities abroad, they will need to continue to be aware of recent and upcoming regulatory changes in Europe and Asia. Some organizations are working to harmonize methods of study, application and review of these products. In the pharmaceutical industry, the International Conference on Harmonization is leading the effort, and the Global Harmonization Task Force is heading the effort for the device community. Their objective will be to reduce variations in regulatory pathways and expectations that are encountered by industry.

Ultimately, there may be one process that allows the submission of the same application package to all target nations. In the meantime, these organizations and their member nations are making great strides to reduce the complexities that industry confronts in gaining access to international markets.

John Sullivan is director of Quality and Implementation at Clinton, MA-based Radius Product Development, where he manages quality and regulatory compliance during product development and launch. John can be reached by e-mailing him at  [email protected].

Henrik Elbaek Pedersen is managing director at Radius Product Development’s Copenhagen office, where he is responsible for the operations, productivity, growth and financial vitality of the company’s European operations. Henrik can be reached by e-mailing  him at [email protected].