FACE TO FACE
President, mdc medical device certification, Memmingen, Germany, and Chairman, ISO TC 194
Writing international standards is anything but easy, especially when one considers the logistics of assembling representatives from various nations and gaining input and agreement from all of those involved. Even so, the importance of establishing a globally harmonized system for medical device regulation is not only well recognized by those in the industry, but doing so may also be critical to the success of device companies in the years ahead.
Aware of these factors, Wolfgang Müller-Lierheim, chairman of the International Organization for Standardization's (ISO) technical committee on the biological evaluation of medical devices (ISO TC 194), is in a position to affect the timely development of one such worldwide standard. In addition to overseeing the committee charged with ISO 10993, Müller-Lierheim has become intimately familiar with international standards through his years as president of a medical device testing company that he founded 16 years ago, as well as in his prior role as head of product development for what has since become CIBA Vision. He has also served on several standards-writing organizations in the device industry and is also involved with the European Commission's working groups related to the practices of notified bodies and other issues concerning medical devices.
In this interview, Müller-Lierheim discusses his vision for ISO TC 194 as well as his thoughts on how ISO 10993 may be used throughout the global device community.
How does the work of ISO TC 194 in the field of biocompatibility relate to other standards around the world?
International as well as national standards are voluntary. Under the so-called new approach, harmonized standardswhich are European standards that have been referenced in the Official Journal of the European Communitiesplay a key role in the European system of directives. European authorities, including notified bodies, have to assume that a product complies with the essential requirements of the relevant directive addressed by a harmonized standard if the product meets the requirements of that standard.
The European Committee for Standardization (CEN) obtains mandates for the development of harmonized standards from the European Commission. The ISO 10993 series of standards addresses the commission's mandate for the development of harmonized biocompatibility standards for medical devices.
We now have two committees that handle the biocompatibility of medical devices. One is CEN TC 206, which is the European committee in the medical device field, and the other is the international committee, ISO TC 194. As we see in other fields of international standardization, it is not always clear whether the majority of delegates of technical committees are moving toward international harmonization or whether they're choosing to stay with their own American, Japanese, Chinese, or European ways.
In the case of ISO TC 194 and CEN TC 206, we are fortunate that CEN TC 206 has agreed that this mandated standard should be created on an international level, so long as the ISO committee is able to obtain approval for an international standard and meet the time goals that have been set by the European Commission.
How does the work being done by ISO TC 194 relate to standards in countries outside Europe?
First of all, the work of ISO TC 194 started with looking at what existed. The entire work of the ISO 10993 series started with the so-called Tripartite Agreement adopted by the United States, Canada, and the United Kingdom. And until May of last year, this agreement was the basis of biocompatibility assessment by FDA.
During 1989 and 1990, we reviewed the standard and tried to identify its strengths and weaknesses as well as what was lacking. Working groups (WGs) were then formed to review and improve on what existed. The result of their efforts became ISO 10993-1, which was then adopted as an AAMI [Association for the Advancement of Medical Instrumentation] standard in the United States and later replaced the Tripartite Agreement for FDA use.
That's ISO 10993-1, on the selection of test methods?
Yes, that's the one adopted by FDA. And some other parts have also been adopted by AAMI.
ISO 10993 was originally expected to contain only 12 parts but has now expanded to include 16. Does TC 194 plan to continue evaluating what biocompatibility standards are needed within ISO 10993 and add sections accordingly?
On that, I can only give you a very personal opinion. We started with what we thought was most urgently needed. About a year ago, we reached a point where we had covered most of the issues and thought about how these standards are used internationally. We concluded that some standards work might still be needed.
On the other hand, the existing documents were developed under quite a bit of time pressure, and we were aware from the beginning that an early revision would be necessaryespecially because all the standards were being developed simultaneously and would need to be checked against each other for consistency.
Was the time pressure because of the CEN mandate?
Yes. The European Medical Devices Directive (MDD) became effective on January 1, 1995, and we have a transition period until June 13, 1998, after which all medical devices have to be CE marked and assessed. There is no grandfather clause in Europe, so all devices will have to be evaluated.
So that put pressure on the committee to complete the initial group of standards so they could be referenced in the MDD?
Harmonized standards are not directly referenced in the MDD but become "harmonized" by reference in the Official Journal of the European Communities. The time pressure is associated with the deadlines defined in the European Commission mandates given to CEN.
ISO 10993-1:1992 was accepted as a European standard and published as EN 30993-1 in September 1993, meaning that it has been recognized by CEN. But in order to become a so-called harmonized standard, it has to be recognized by the European Commission, which is the governing body for Europe. The standard will be considered harmonized only after it has been published in the Official Journal of the European Communities, and this is still pending.
ISO TC 194 managed to publish ISO 10993-1 as early as 1992only three years after the technical committee's establishment. Regulatory authorities accepted this international standard, but not without slightly modifying the approach. FDA put in some additional requirements, Japan provided additional guidance, but the European Commission has not yet decided that ISO 10993-1 is a harmonized standard, although other parts of ISO 10993 have been recognized as such.
Does that mean that TC 194 needs to go back and revise ISO 10993-1 to take into account what FDA and the Japanese have done?
Yes and no. TC 194 recognized that the extent of guidance given in ISO 10993-1 was not sufficient. We discussed two options: either completely revise ISO 10993-1 to include all the variations brought in by different parties or initiate a minor revision and address the additional need for guidance in a separate part of the standard. TC 194 favored the second option, so we established WG 15 to develop a strategic approach to biological assessment of medical devices.
Because it was very important to get all parties involved, we had the people responsible in FDA attending the meeting in Stockholm last April. And they demonstrated that they were prepared to discuss their ideas and concerns with the international community. The Japanese government representative was also available to discuss a fair way of interpreting the document, so having this meeting in Europe with the two regulatory bodies was a very positive situation.
FDA supported the development of ISO 10993-1 but decided to modify it for implementation in the United States, placing U.S. manufacturers in the awkward situation of still not having a harmonized standard. Will this new effort with the agency's involvement be likely to erase that discrepancy?
I am sure we will be able to find an international agreement, because the question of a person's safety cannot be different in Europe, the United States, or the Far East. It's only the way of thinking that's different. Even if there are five experts from FDA involved in the development of a standard, it does not necessarily mean that they reflect the opinion of the whole organization.
On the other hand, with international standards, we have involved regulatory authorities, industry, health professionals, and patients, and they all have their own interests, peers, and constituencies. So every international standard is a compromise of the whole community. Now assume that five representatives of one large organization have done their best to achieve an optimum-quality standard. It does not necessarily mean that they do not get criticism from their own organizations. That's just the way it is. We have to find what's best for an internation- al community, and I'm quite sure we will achieve it.
How are the ISO and European standards' voting and adoption systems structured?
There are more than 150 national member bodies within ISO. A majority of qualified votes in ISO means that an ISO document is adopted. In this case, the United States has one vote, just like Israel or Zimbabwe.
By contrast, there are only 18 members of CEN. And the European standardization system has a weighted voting process, so larger countries have more votes than smaller countries, although we have strong protection of minorities. We need much more consensus in Europe to get a standard.
Additionally, an ISO standard is absolutely voluntary; individual countries are free to decide whether to adopt it as a national standard. It's completely different in Europe; every European standard has to be transformed into a national standard within six months of publication.
This is a tight schedule, and it means that if there is a European standardwhether or not it differs from an ISO standardthe European standards bodies have no choice but to accept it. Adopting the ISO standard or any other standard is not an option. This is why it is so fortunate that TC 194 has a good relationship with its sister committee, CEN TC 206, under the so-called Vienna Agreement.
You mentioned the new WG 15. How is it structured?
TC 194 decided to establish a management team for WG 15, with one representative each from the United States, Japan, and Europe. We also wanted to be sure that there would be an equilibrium between industry and government. For example, Akitada Nakamura from Japan is a leading member of the Japanese regulatory body, whereas Barbara Krug is a representative of European industry. Barry Page from the United States, who was given overall convenorship, is from neither government nor industry, although he has a history in industry with Becton Dickinson as well as with the Health Industry Manufacturers Association. He is very well known and has a good track record in international standardization work. He was formerly convener of TC 194/WG 11, which was responsible for compiling 10993-7 on ethylene oxide residuals.
Also, Pauline Mars from the Netherlands is the secretary, so we really linked ISO TC 194 to the different economic areas, as well as to the European standards work.
So the working group is structured such that it receives the necessary input to ensure that when it's finished, everybody has signed off on it?
This is what we tried very hard to do. Forming such a group was not easy.
In looking back at ISO 10993-1, what has the committee found to be missing?
ISO 10993-1 clearly states what is needed in medical device biological evaluation, and one of the requirements is to consider existing information. While the standard includes this as a requirement, it does not give sufficient guidance on how to do it. Now, in this kind of a vacuum, an FDA group under the direction of Mel Stratmeyer developed a draft proposal on how to use existing information. The document is an interesting and thoughtful approach, and we wanted to include it in our international discussion because it was, to my knowledge, the first paper that extensively addressed this aspect.
FDA had hoped to revise that document for issuance as a guidance for U.S. industry. Will using it as the basis for a larger international framework give the document more importance than it might otherwise have had?
Absolutely, and I understand that FDA is willing to accept input from other countries and experts to improve the document to where it can achieve international acceptance. And that is exactly what we aim to do as an international community and committee.
So last December's draft guidance has provided a starting point for the work-ing group. Where do you expect it will go from there?
There is one more point that is missing in ISO 10993-1. We assumed we had a guidance on how existing information was to be used, as well as a guidance on which tests may have to be performed. But there is not sufficient guidance on how to interpret test results, so this is another issue that WG 15 should address.
One approach is to say, "This is the individual expertise of the so-called expert." But why shouldn't we try to formulate part of a standardized way to assess test results? It will certainly take time to resolve this issue.
Another point that is not clearly addressed is the question of materials characterization. This also relates to Mel Stratmeyer's paper on how to use existing information, but WG 14 under the convenorship of John Lang from the United Kingdom would have to address how to do that from a scientific point of view.
How does the work of TC 194 relate to FDA's planned biomaterials compendium, and what level of characterization do you think is needed for the materials used in medical devices?
To our way of thinking, the materials manufacturer should be primarily responsible for providing the level of materials characterization necessary to begin biological assessment. So this information should be released to the device manufacturer, but it should also remain proprietary.
All we want to standardize is the kind of data that must be provided in order to start assessment. Frequently, a test report will describe a test method and result but will not clearly say what kind of material has been tested. This leads one to ask whether the material really is representative of the product that comes onto the market. If a regulator gets a test report, how does he or she know that it really relates to the product entering the market?
There has to be some guidance given on how to describe the product. There are different ways to do that. One way would be for the manufacturer to keep on file the exact characterization of a material that relates to a certain batch number, or something like that, and then give the test results. Another way would be for a manufacturer to disclose this information to the test lab, or for the test lab to perform its own characterization of the materials. In no way has this been resolved; it must still be addressed.
Another area where we found weaknesses relates to the question of reference materials. There is not a sufficient number of well-characterized reference materials and positive and negative controls for all types of biological evaluation. We became aware of this during compilation of the standard on material preparation and reference materials. So in this case it is not sufficient just to revise the document; some basic work still needs to be done.
And last but not least, the whole issue of biological evaluation has evolved from the testing of chemicals. Some of the test methods we are currently using have been validated for chemicals and active substances but not for medical devices.
The question of sample preparation has to be addressed by the working group on sample preparation, and the validation of test methods has to be coordinated by each individual group describing these methods. This will not change the committee's work in principle, but it will make the standards more understandable to those parties that were not directly involved in their development. They will become more evident to both regulators and to industry, and I think this is necessary.
One of the ways FDA modified ISO 10993-1 when it accepted the standard was by including a flowchart to lead people through the process. Are working groups planning to incorporate similar information?
Yes. WG 1, which is responsible for ISO 10993-1, is including a flowchart now. The working groups are willing to include whatever intelligent input they obtain. Similarly, international standards committees should review whatever ideas are available, and mem- bers of working groups should apply their national experience.
Do the committees have problems dealing with the FDA approach because FDA is a regulatory body and not a standards-setting body?
Not necessarily. It may create problems, but the ways assessments are done in different regulatory areas will eventually be harmonized. Part of the contribution of an international standards committee is to question the ways in which assessments are made. Even without TC 194, every regulatory authority is changing, and the way FDA made assessments in the 1980s is not the same as in the 1990s.
So this is very much an ongoing process of feeding in new information and then using it to improve the standards that are written and the way they're used?
Definitely. And all the members of these international committees have to learn about the differing systems of various countries. There are some countries, like the United States, with very well developed systems, and there are others that are still learning. Nevertheless, maybe those countries that are still learning will simply improve on all that exists in a well-operating system.
Are other nonmembers watching what the committee does, or do they think its efforts don't apply to them?
I doubt nonmembers feel that the committee's efforts don't apply to them. It's more an economic question of whether a country can afford to have a sufficient number of well-trained experts as well as resources for international travel. This is clearly a situation in which only the developed countries can afford to have people directly involved in the standards writing. Other countries are watching and using some of the work, but they're not participating actively.
What about the way the tests for biocompatibility and so on are accepted internationally? Presumably a U.S. company would be able to submit its device for a specific required test and, once that has been successfully accomplished, the results would be accepted internationally, without question.
That is exactly the aim. We now have one major difference between the U.S. and European systems of assessment. In the European system, the MDD requires that each manufacturer make its own risk assessment, which is not currently required by FDA.
While this is a minor difference, the European system is based on the assumption that manufacturers should have sufficient expertise to be the best people to evaluate their products. Only if the manufacturer's own risk assessment seems to be weak does the notified body have to interfere. If the product is Class III according to the MDD, the notified body does have to take a thorough look at the assessment and follow it, whereas with low-risk products more responsibility lies with the manufacturer.
As I understand it, in the U.S. system the responsibility for risk assessment is mainly put on the shoulders of FDA.
So the manufacturer should be able to test its own devices but, in cases where a third-party independent assessment is required, a testing house is used?
Yes, but the manufacturer is not expected to have all test facilities in-house. Rather, it is expected to have sufficient understanding of its own products to be able to decide which tests have to be performed and to select the appropriate testing houses.
While many Americans are familiar with the term notified body, they are still confused when it comes to exactly how those bodies function.
A notified body has two tasks: certification of quality management systems, and certification of the performance and safety of products. Certification of the performance and safety of products does not necessarily mean that the notified body has to perform the tests itself. Rather, it must be capable of showing that the tests that are done are done properly, and give sufficient evidence of the product's safety and performance. The European system of accreditation and certification gives an opportunity for a testing house to be accredited by the government for certain tests.
For example, you'd have to go to a notified body that was notified for the electromagnetic compatibility (EMC) directive in order to have that body go to a testing house; the notified body couldn't do the testing for EMC itself?
You see, FDA never does tests itself; it accepts test results from others. Nevertheless FDA is expected to have the expertise to judge the results. It's much the same with notified bodies, although they have an option to operate and employ in-house test facilities.
So FDA is more like a combination of competent authority and notified body?
Yes. The whole area of postmarketing surveillancein the United States it's called the medical device reporting systemis the competent authorities' business in Europe. Notified bodies are not directly involved. So it is just that the task has been divided in Europe among different groups.
In Europe, are there standards that a testing house for biocompatibility and toxicology would have to meet in order to be considered acceptable?
In Europe, the standard, as such, does exist. It's not only for biocompatibility, it's for all kinds of third-party testing. We have the European standard, EN 45001, and this outlines how to operate a test laboratory. It is similar to ISO Guide 25, and as I understand, ISO Guide 25 is now under revision to be more harmonized with EN 45001.
Are those the equivalent of the good laboratory practices (GLP) regulation in the United States?
Yes, but ISO Guide 25 is closer to EN 45001 than to the GLP regulation. For example, EN 45001 gives clear guidance on how a test lab must demonstrate its independence from commercial interests. The GLP says more about organization.
How does this work if the lab is in the United States?
This is one of the major difficulties we have to resolve: how can a European notified body make sure that a U.S. laboratory meets the necessary requirements? U.S. laboratories have approached notified bodies and they have reached some agreements in trying to overcome the difficulty, but so far we haven't come up with a very satisfactory solution.
So the United States has to catch up with Europe so that its labs can demonstrate that they are of sufficient quality?
I think some assistance from the U.S. government is needed. If there is a system in place, we can negotiate about common standards, but as long as we do not see a system that we can recognize, it is very hard from a European point of view to distinguish among different U.S. labs. Now what happens is the same thing that happened to European contract sterilizing companies. Those companies did not have a governmental acknowledgment, which meant that they were visited by a number of European notified bodies. And this is somewhat similar to what may happen to major U.S. laboratories.