By: Petra Kaars-Wiele

Although most of the countries claim that their regulation has been set up according to the harmonization guidelines of GHTF or AHWP; in reality, every single country has its own set of regulations, technical requirements, product specifications, data banks, sales controls, and import rules, and every year more countries become regulated—or regulated countries are revising their regulations. There are several political motivations to invest in new regulations: product safety, health protection, funding of health systems, trade agreements, and safe harbor for local manufacturers are some of them. However, there often may be overlap of these different motivations.

The IVD industry has been consolidated due to major acquisitions and mergers. Products have become more complex and sophisticated. Costs to meet worldwide requirements for performance, rules for how submissions files are to be presented, language requirements, and the need for more and highly specialized personnel in regulatory affairs are increasing. Regulators and the IVD industry have difficulties finding additional staff and future leaders in regulatory affairs. Education and training for industry and regulators will become an even more important tool than it was in the 90s.

 

Since the founding of the GHTF in 1992, a complete set of documents for a regulatory framework has been created by a joint effort between regulators and industry. From the premarket phase (e.g., essential requirements, labeling requirements, preparing Summary Technical Documents) to conformity assessment and product listing, documents (including those specific to IVDs) are available or are nearing publication. These also include documents for a quality system for medical devices, as well as auditing, supplier control, and medical event reporting. Basically, the documents cover the major aspects of regulation and what regulators and industry believe is best practice.

Based on this concept, the AHWP has adapted the documents to its needs.

While it would be preferable to invest in one worldwide harmonization effort, it is helpful at least that members from AHWP are guests at GHTF working meetings to ensure convergence of both organizations rather than divergence.

The efforts and good intentions of both organizations cannot be praised enough. Many newly regulated countries are using the GHTF and AHWP documents as the basis for their national regulatory frameworks.

Unfortunately, every newly regulated country and even the founding members of GHTF still have many differences, or different processes until products are approved according to the national regulation. Industry has invested in regulatory and quality personnel and increased the work force to address all these requirements. Fees for registrations have been increased or have been newly introduced. Costs for legal documents are increasing year by year.

Other harmonization work worth mentioning is taking place within the International Standardization Organization (ISO) or the International Conference on Harmonization (ICH). More and more, they play an important role for IVDs, but these groups do not have IVDs as their main focus.

Continuous training and learning are required to support common understanding about the practiced quality system. For example, the concept of a legal manufacturer and its liability and responsibility over the physical manufacturer must be taught; the difference between the country of origin and the place, where the legal manufacturer is based, must be understood also. Requirements for customs and health authorities often conflict. These small day-to-day challenges, when combined, are quite a bit for the IVD industry to deal with and to continue to deal with when efforts of common learning and understanding are not strengthened.

While an umbrella of rules and requirements is now available, and countries claim to work according to these, it does not automatically mean that the requirements are understood or the processes are the same. Therefore, the harmonization activities at GHTF, AHWP, ISO, ICH, and others must continue.

 

Since the transposition of the IVD Directive in most of the EU countries in 2000 and the end of the three-year transition period in December 2003, several initiatives have supported and improved the safety and effectiveness of IVDs in the European Union, like the introduction of Common Technical Specifications (CTS) for high-risk IVDs listed in Annex II of Directive 98/79/EC in 2003 and the recent revision in 2009.2 The European Union has grown from 15 member countries to 27. An additional four countries of the European Free Trade Association (EFTA) have fully adopted the EU regulatory requirements.3 The principles of the IVD Directive and the free movement of goods are major achievements for this important trade area. In parallel, we have seen new regulations becoming effective and affecting IVDs: registration, evaluation, authorization and restriction of chemicals (REACH), waste electrical and electronic equipment (WEEE), restriction of the use of certain hazardous substances in electrical and electronic equipment (RoHs), and the animal by-product regulation.4-7 The last one may have implications for animal materials used or where the product is manufactured.

 IVDs have not been the main target for these new regulations. The regulators had different industries (e.g. chemical or computer) in mind while working on these regulations. Even the IVD industry did not imagine it would be affected by these new requirements at first, or they believed IVDs would be exempted. It requires highly specialized resources to understand and comply with these regulations. These new requirements are environmentally driven and may not be relevant to increase product quality or safety of IVDs.

 

Today, translations of at least 22 local languages are required according to national legislations. A major simplification for the IVD industry during the past 15 years is the publication of the MedDev document 2.14/3, rev.1, which allows manufacturers in the EU to use other means for distribution of instructions for use (IFU).8 Instead of distributing paper versions, CD-ROMs can be provided or manuals or IFU can be published via the Internet for professional users. This can result in significant savings for IVD companies. The significant cost for translations remains. Prior to 15 years ago, package inserts were provided in only five languages.

Also, the medical device industry has realized in recent years that advertising and promotion are important elements of labeling. Increased requirements and recent warning letters in the United States motivated the industry to introduce better processes and to ensure compliance and consistency with the claims of the products.

The medical device industry has seen a tendency to introduce laws and regulations that require advertising and promotional material be submitted and approved and subject to increased scrutiny by authorities (in China and Saudi Arabia, for instance).

 

All the new members of the 27-member EU became regulated. Creating a new common market in Asia with ASEAN has resulted in all 10 member states becoming regulated. Even if they harmonize their regulations in the future, we will see a variety of different processes for approving products in that commercial area. Saudi Arabia set a new standard for the Middle East and introduced regulations for IVDs in 2009. The United Arab Emirates have followed that example and introduced their framework of notification and product approvals in 2009. Other countries in the region have announced they will also follow this course. Australia has expanded its current legislation to regulate IVDs as of this year. Most of the South American countries have been regulated, and countries in Central America have followed suit as well.

 

For industry, auditing is an integral part of the Quality System (QS) for improving processes and a proof that the established system is sustainable. Every company has gained major improvements with the introduction of QS to their business.

Several political systems have introduced QS requirements into their legislation and integrated audits as a part of product approvals. The trust level in a certified Quality Management System (QMS) seems to be low; therefore, industry has experienced more and more audits by regulators.

Auditing by regulatory bodies has been seen as a tool to control industry. Unfortunately, companies may have experienced conflicting observations and views from regulators from different nations. The intensity and the frequency of regulatory audits have made this an additional burden for industry. The burden to industry is not only the costs, but also the time required of the regulatory and QS personnel to prepare for preaudit requests, support the audit, entertain the auditors, and perform the follow-up items as required. To date, the following countries audit companies worldwide and outside their own jurisdiction: Australia, Brazil, Canada, Japan, and the United States. Other countries are preparing for their legislation to integrate QS requirements and allow worldwide audits of the medical device industry.

Another increasing trend is that customers from regulated areas (e.g., blood banks, accredited laboratories) are performing audits of the IVD manufacturing sites to fulfil the requirements of their own quality systems.

 

In the last 15 years we have seen great leaders in regulatory affairs in industry and government. However, many of them have retired or are close to retiring. To avoid a major gap in leadership, the IVD industry has to be ready to invest more in training, not only for newly regulated countries or emerging markets, but also within the Western Hemisphere. Organizations like Regulatory Affairs Professional Society (RAPS) and industry associations (e.g., Japan Association of Clinical Reagent Industry, European Diagnostic Manufacturers Association, AdvaMed) will have to continue to play an important role in that field. Conferences, working groups, training classes, and certifications are all important tools we should continue to use and improve on for training purposes.

The harmonized elements of IVD regulation and the assurance that safe and effective products are sold in the market are available because of the tremendous efforts of GHTF and AWHP. Now regulators with industry support have to concentrate on simplifying the processes, supporting mutual recognition agreements among the countries, and allowing industry to continue to improve existing products and increase their efforts toward developing new, innovative products for the well-being of everyone.

 

1. ISO 13485:2000, “Medical Devices—Quality Management Systems—Requirements for Regulatory Purposes.” (Geneva: International Organization for Standardization, 2000).

 

2. “Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on In Vitro Diagnostic Medical Devices,” Official Journal of the European Communities L 331/1 (1998).

 

3. EFTA countries are: Iceland, Liechtenstein, Norway, and Switzerland.

 

4. Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), establishing a European Chemicals Agency, amended by several Directives and Regulations.

 

5. Directive 2002/96/EC of the European Parliament and of the Council of 27 January 2003 on waste electrical and electronic equipment (WEEE).

 

6. Directive 2002/95/EC of the European Parliament and of the Council of 27 January 2003 on the restriction of the use of certain hazardous substances in electrical and electronic equipment.

 

7. Regulation (EC) No 1774/2002 of the European Parliament and of the Council of October 2002 laying down health rules concerning animal byproducts not intended for human consumption, amended by nine papers. Note: There are additional four regulations amending the 1774/2002, which are not added to this list due to length and complexity. Any questions regarding these may be sent to the author.

 

8. MedDev 214/3 rev.1, January 2007: IVD Guidance: Supply of Instruments for use (IFU) and other information for In-Vitro Diagnostic (IVD) Medical Devices – A Guide for Manufacturers and Notified Bodies.

 

Petra Kaars-Wiele, PhD is director, International Regulatory Affairs & Affiliate Compliance at Abbott GmbH & Co KG (Wiesbaden, Germany). She can be reached at Petra.Kaars-Wiele@abbott.com.