Originally Published MDDI May 2004
Originally Published MDDI May 2004
An increasing number of companies are offshoring clinical research to Europe. But is that the best way to prepare a device for release in the United States?
Nancy J. Stark and Jeff Peacock
Globally speaking, the typical event progression for manufacturers wishing to sell a medical device is to first conduct clinical studies in Europe to obtain a CE mark. Then they do clinical studies in the United States to obtain FDA clearance.
There are many examples of new technology devices that were on the market in Europe for years before they received FDA clearance or approval. Some examples include the Lung Assist artificial lung from NovaLung GmbH (Hechingen, Germany), the Prodisc artificial spinal disc from Spine Solutions (New York City), the Aquamid injectable soft-tissue filler from Contura SA (Soeborg, Denmark), and the Magic Box stent-coating machine from Translumina GmbH (Hechingen, Germany).
Understandably, new technology devices are first introduced in Europe when a European company develops the device. But it is increasingly common for U.S. manufacturers to conduct their first clinical studies in Europe to obtain a CE mark, and then continue with U.S. clinical studies and regulatory submissions at a later date. Some companies have attempted to gain FDA approval for their devices based solely on European data, and a few have been successful. Q-Med (Uppsala, Sweden) gained approval for Deflux, for treatment of vesico-ureteral reflux in newborns, based solely on European data.1 Coloplast Corp. (Humlebaek, Denmark) obtained a 510(k) clearance for Contreet, an antimicrobial wound dressing, also based solely on European data.2 A few orthopedic products have also been successful with this approach.
The general hope is that FDA approval will come more easily and with a lowered hurdle for U.S. data if evidence from a well-controlled European clinical trial is available. This article reviews some of the attitudinal differences between Europe and the United States that affect the ease with which U.S. manufacturers can do research overseas.
Laws and Regulations
In the European Union (EU), three directives primarily regulate medical device clinicals: the Active Implantable Medical Devices Directive, the Medical Devices Directive, and the IVD Directive. A directive is passed by the European Commission but does not become a member state law until it is transposed. Transposition is similar to ratifying a treaty. Transposition involves:
• Renumbering the paragraphs of the directive to conform with local format.
• Translating the text into the member state's language.
• Adding any elements the member state deems appropriate.
The last feature reintroduces the variability that Europe had hoped to eliminate by forming a union; the directives serve only as a baseline for medical device regulation. Each member state is free to add any regulatory requirements it deems appropriate, and thus each member state differs in its regulation of medical device clinical research.
Nevertheless, there are commonalities. In all European countries, both competent authority approval (usually the Ministry of Health) and ethics committee approval are required prior to study initiation. Usually, a copy of the ethics committee approval must be provided to the competent authority. The competent authority has 60 days from the date it receives the application to ask whatever questions it may have. If no questions are forthcoming and 60 days have elapsed, the sponsor may assume approval. This so-called silent approval system is used in a few countries, but most will actively send a letter of approval.
Like the U.S. FD&C Act, the directives don't say a great deal about the specifics of clinical research. For details, manufacturers must turn to the harmonized standard ISO 14155, Clinical Investigation of Medical Devices for Human Subjects—Part 1: General Requirements and Part 2: Investigation Plans.3 It is important to note that, unlike U.S. regulations, compliance with harmonized standards is voluntary.
Compliance with a directive or transposed law may be met in other ways; for example, one manufacturer had its medical officer, rather than the investigators, sign the final report. The practice saved time and met the Medical Devices Directive essential requirement that “the written report [be] signed by the medical practitioner or other authorized person responsible.”4 This voluntary status gives sponsors leeway in terms of actual study conduct. Of course, the Declaration of Helsinki should be followed for all clinical research.
One important note regarding the regulatory process in Europe is the disconnection between study approval by the competent authority and product approval by the notified body. The competent authority of the host country reviews the protocol and study documents and then grants permission to conduct the clinical study.
The data and study conclusions are never reported back to the competent authority. Instead, the data and final report are made available to the notified body as part of the technical file to support the CE mark. Most notified bodies are not educated in clinical research, and there are no FDA-like reviewers to withhold product approval until reliable clinical data are made available. This absence of review may explain why the quality of clinical research in Europe remains low.
Shorter Time to Study Initiation
The primary reason for conducting trials in Europe is the shorter study protocol approval time. Because the European sites are likely to be finished before the U.S. sites begin, it is rare for companies to pool data from European and U.S. investigative sites.
In Germany and The Netherlands, for example, the protocol can be submitted to both the competent authority and the ethics committee simultaneously. As soon as ethics committee approval is obtained, the approval letter is forwarded to the competent authority and the study can begin. Because the United Kingdom has the most technically sophisticated competent authority, it is the most likely to ask questions regarding a study plan. Italy has some of the most innovative physicians in Europe, but study approval is slower and more bureaucratic.
Study costs fall into three categories: monitoring and contract research organization (CRO) costs, investigative site costs, and ethics committee costs. Monitoring and CRO costs are generally less than those in the United States, taking into account the exchange rates. For example, monitoring for a 20-subject study was bid at $133,000 by a U.S. CRO; the same study was bid at $156,000 by a Swiss CRO and $45,000 by a Dutch CRO. Ethics committee costs run about the same as U.S. IRB costs, at about $2000 per study.
Investigative site costs tend to run much lower per subject in Europe than in the United States, from $1000 per subject in Europe to $3000 per subject in the United States; this is where manufacturers experience a real cost savings.5 Investigators in Europe are not accustomed to high payments per subject, and they frequently conduct studies at no subject fee whatsoever. This translates to a big savings if the study involves a few hundred subjects. Countries farther east have the lowest subject cost, but their populations and standards of care are the least similar to those in the United States.
Study costs should not be considered in isolation, however. There is a down- side to conducting trials in Europe. European investigators tend to act more independently than those in the United States. For example, in one case a European-born investigator refused to allow access to source files, stating, “I'm the professor”; in another case, a German investigative site insisted on being the investigator-sponsor to avoid outside monitoring. Europeans often do not feel the commitment to protocol compliance to which U.S. sponsors are accustomed. U.S. investigators tend to be more businesslike, delivering a product for profit.
Time to Complete Studies
Studies done in Europe are completed in roughly the same amount of time as in the United States. However, investigators may not feel the same commitment to inclusion and exclusion criteria as those in the United States. So, although the study quota for subjects may be reached sooner, it's possible that not all data will be evaluatable.
Patient Privacy Issues
Europe has privacy concerns similar to those of the United States by virtue of the Directive on Privacy and Electronic Communications.6 The gist of the European directive is that a subject's medical information may be collected for clinical research purposes (with informed consent, of course), but the data may not be exported to the United States unless the importing sponsor is compliant with HIPAA or the safe harbor principles espoused by the U.S. Federal Trade Commission.7
Patient Recruitment and Patient Fees
Europe lags behind the United States in its comfort with public announcements of clinical trials. Advertisements for subjects in the Sunday paper, on public transportation, or over the radio are less common in Europe than in the United States. Most subject recruitment is handled through networking among investigators.
Patient fees, or direct payments to patients or subjects, are very low. Europeans have a different attitude toward paying for participation in research. They are very concerned that payments may be coercive or unduly influential. Such payments, therefore, are frowned upon. A trial sponsor might be able to compensate a patient for travel and parking, but the amount must be disclosed to the ethics committee for its approval.
Quality of Investigators
European physicians are among the finest in the world, and their delivery of healthcare is topnotch. Their access to the latest medical technology is a decade ahead of the United States, and they are comfortable with innovation and willing to try new technologies.
The European directives, however, are only a decade old, and the attitude toward clinical research is comparable to the early U.S. regulatory era of the 1970s. Manufacturers are far less likely to find sophisticated research clinics, investigators with a respect for the regulatory aspects of good clinical practices, dedicated research staff or research coordinators, and investigative sites. CenterWatch's Web site shows approximately 850 U.S. investigative sites, compared with only about 30 international sites listing their services.8 In addition, any clinical study in Europe should provide for frequent (every 2–3 months) and in-depth (100% source verification of data) monitoring.
Quality of Data
It is well accepted by U.S. sponsors and regulators that the quality of data from Europe is more variable than that from the United States. (“Quality” data are defined in FDA's Guidance for Industry: Computerized Systems Used in Clinical Trials as data that are accurate, complete, logical, legible, contemporaneous, and attributable.) European sponsors and investigators do not share this sentiment, of course. In an informal poll, U.S. monitors said they believe the average 200-subject study has around 10,000 errors. European monitors said they believe the average 200-subject study has around 1000 errors. Is the difference that U.S. investigators make more mistakes, that they are more aware of them, or that their studies are judged by a different standard?
FDA's most common objection to European data is related to how representative European subjects are of the U.S. patient population. Concomitant illnesses may be reported differently; for example, hypotension is a commonly treated disease in Germany, but it is not recognized as a disease in the United States. Drugs may be reported under different names and may not be recognized by FDA. Herbal medications or home remedies may be used differently and not reported, and personal hygiene practices may be different. Furthermore, disease status may have progressed further in countries with long waiting lines for access to medical care. Trial sponsors should be prepared to justify to FDA why the European clinical data are applicable to U.S. medical practice.
Nevertheless, much can be learned from European data, and sponsors who wish to initiate a clinical study there should not be discouraged. Good-quality data that will move a product toward a speedier FDA approval can be obtained from Europe. It is critical to select investigators who are accustomed to doing clinical studies for pharmaceutical companies and pay them. It is equally important to hire a CRO familiar with U.S. medical device regulations.
Final reporting works differently in Europe than it does in the United States. In the United States, each investigator prepares a final report of the events as they occurred at that particular investigative site. These final site reports are sent to the IRBs and to the sponsor. The sponsor, in turn, collates the final site reports into a statistically valid study report, which becomes the final study report provided to FDA.
In Europe, the sponsor prepares a final study report and routes it to each investigator for signature. Investigators review the report for the entire study and must sign before the study is considered complete. Alternatively, sponsors must explain the absence of an investigator's signature. The signature process is a cumbersome burden—but staunchly protected by the investigators—and sometimes takes longer than the study itself.
European investigators have a different attitude toward publication than U.S. investigators. Europeans feel strongly that all clinical data should be published; this feeling probably dates back to the events of World War II. They will argue that, ethically, even negative data should be published, and investigators will insist on their right to do so. In fact, ISO 14155 Part 1, Section 11.1 states, “A final report of the clinical investigation shall be completed, even if the clinical investigation is prematurely terminated,” and Section 4.13 states that “it is highly desirable that all results should be offered for publication in scientific journals.”
Europeans do not recognize early development studies as clinical studies. In this way, they legitimize not publishing data on prototype designs. It is important to sort out publication rights and responsibilities with investigators prior to study initiation.
Ethics Committee Requirements
Ethics committees in Europe operate much the same way that IRBs do in the United States. The biggest difference is that the committees are created top-down—each competent authority divides its country into geographic regions and creates an ethics committee to serve each region. Several countries have a two-tiered system consisting of a local, hospital-based committee and a national committee. In those countries, studies are reviewed at both levels. The local committee is usually charged with reviewing the qualifications of the investigator for that particular study. The national committee is charged with reviewing the study for scientific and technical merit. Countries with two-tiered systems include the United Kingdom, The Netherlands, and Denmark.
Germany has an interesting legal- political situation. Its transposed directives provide for local ethics committees and independent (for-profit) ethics-committees. The independent committees are easier and faster to use, and they have the legal authority to grant approval for a study throughout Germany. However, many local ethics committees do not accept such approvals, and thus can effectively block studies from starting until local approval is obtained.
In France, ethics committees are known as Consultative Committees on the Protection of Persons in Biomedical Research (CCPPRBs). Approval from one CCPPRB grants approval to conduct the study at any site in France.
Trial sponsors should not overlook the fact that every country in the world besides the United States requires sponsors to carry clinical research liability insurance. The requirement makes sense because most countries provide public health services; the state doesn't want to be stuck with the bill in the event subjects are injured by an investigational device or the sponsor goes out of business. In France, for example, the government has the right to sue a sponsor for recovery of medical costs if a subject is injured in a study.
Many countries even require the underwriter to be located in the host country. Trial sponsors must provide a copy of the insurance certificate to the ethics committee. Fortunately, insurance isn't hard to obtain. Large firms, such as Lloyd's of London, have offices in every EU country. A rider can be added to a policy for each country in which coverage is needed.
Offshoring clinical research activities to Europe is going to continue. The region provides well-trained investigators, adequate subject availability, ease of study approval, minimal regulation and oversight of ongoing activities, and cost-effective data acquisition. European trial regulations are changing, so in time standards and rigor of clinical trials in Europe will be on a par with those in the United States. Although data quality questions and dissimilar demographics may pose a problem, a European study's data can provide a solid foundation that may justify a smaller U.S. study for FDA clearance of a device. Finally, the shift toward standardization will continue to narrow the gap between European and U.S. clinical trials.
01. FDA/CDRH Gastroenterology and Urology Devices Panel, Advisory Panel Meeting Minutes, Oct. 19, 2000; available from Internet: www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfAdvisory/details.cfm?mtg=174.
02. Coloplast Ltd., “Contreet Foam and Hydrocolloid Antimicrobial Dressings”; available from Internet: www.coloplast.co.uk/Ecompany/GBMED/Homepage.nsf/1989cec9be30ee68c12569ff003696d/d20858e487c8d86780256df7003208f0?OpenDocument.
03. International Standards Organization, ISO 14155-1:2003: Clinical Investigation of Medical Devices for Human Subjects—Part 1: General Requirements, Feb. 26, 2003; available from Internet: www.iso.ch/iso/en/CatalogueDetailPage.CatalogueDetail?CSNUMBER=31723&ICS1=11.
04. “Council Directive 93/42/EEC of 14 June 1993 Concerning Medical Devices,” Annex X, Section 2.3.7, Official Journal of the European Communities, L 169, 199.
5. Nancy J Stark, “Clinical Research Practices in the Device Industry” (Chicago: Clinical Device Group, 2003); available from Internet: www.clinicaldevice.com/13FinalSlides03_files/frame.htm.
6. “Directive 2002/58/EC of the European Parliament and of the Council,” Official Journal of the European Committees, L 201/37, July 12, 2002; available from Internet: www.europa.eu.int/eur-lex/pri/en/oj/dat/2002/l_201/l_20120020731en00370047.pdf.
7. International Trade Administration, “International Safe Harbor Privacy Principles,” Draft, Apr. 19, 1999; available from Internet: www.ita.doc.gov/td/ecom/shprin.html.
8. Thompson CenterWatch, “Profiles of Centers Conducting Clinical Research,” Apr. 9, 2004; available from Internet: www.centerwatch.com/professional/proflist.html.
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