It’s still a big world—at least as far as health care regulations go. Yes, travelers complain of cultural sanitization: Globalization has brought McDonald’s to Egypt, KFC to Singapore, and Pizza Hut to Jamaica. But despite the best intentions and more than a decade of effort, the Global Harmonization Task Force (GHTF) has been stymied in its efforts to smooth the way to the global market for device manufacturers.

Achieving harmonization in medical regulations is an objective with some fairly significant barriers. Regulatory agencies operate under laws; changing them requires new legislation—not to mention the time and bureaucracy that go along with it. “These systems can’t be changed just because we ‘feel like it.’ The law does not allow that,” says Larry Kessler, ScD, director of the office of science and engineering laboratories within the FDA’s Center for Devices and Radiological Health (CDRH of Rockville, Md). “It’s very prescriptive in terms of medical events, so trying to harmonize among nations with different laws is difficult.”

It might be difficult, but it isn’t impossible. In fact, many believe it is inevitable. “Harmonization is definitely the wave of the future. It’s good for the industry, the FDA, and foreign governments,” says Peter S. Reichertz, Esq, an attorney with Sheppard Mullin Richter & Hampton LLP (Washington, DC). Reichertz is leader of the firm’s Food and Drug Law Group.

Synchronize Your Regulations
The Global Harmonization Task Force (GHTF), whose chair is headquartered in Brussels (Belgium), is developing guidances with the intent of bringing the nations of the world in alignment with one another on medical device regulations. Five Study Groups have been charged with developing these guidances.

Study Group 1 is comparing operational medical device regulatory systems around the world, with a focus on suitable elements for harmonization as well as potential obstacles. The group also is charged with developing a standardized format for premarket submissions and product-labeling requirements. SG1 has published such guidelines as:

  • Labeling for Medical Devices;
  • Information Document Concerning the Definition of the Term “Medical Device”;
  • Essential Principles of Safety & Performance of Medical Devices; and
  • Role of Standards in the Assessment of Medical Devices.

Study Group 2 is reviewing reporting, surveillance, and other supervisory elements to converge data-collection and reporting systems. This group has published documents that include:

  • Review of Current Requirements on Postmarket Surveillance;
  • Summary of Current Requirements for Where to Send Adverse Event Reports;
  • Medical Device Postmarket Vigilance and Surveillance: Proposal for Reporting of Use Errors with Medical Devices by their Manufacturer or Authorized Representative; and
  • Medical Device Postmarket Vigilance and Surveillance: Timing of Adverse Event Reports.

Study Group 3 is doing the same as SG2, but for quality control, identifying areas where harmonization can occur. It has published documents on:

  • Implementation of Risk Management Principles and Activities Within a Quality Management System; and
  • Quality Management Systems—Process Validation Guidance.

Study Group 4 is developing guidance documents for auditing quality systems. Group 4 has released guidances that include:

  • Guidelines for Regulatory Auditing of Quality Systems of Medical Device Manufacturers—Part 1: General Requirements;
  • Audit Language Requirements; and
  • Training Requirements for Auditors.

Study Group 5 is handling promotion and guidance of definitions, clinical investigation reports, and clinical evaluations. It also is reviewing documents created within the other groups to maintain a clear and consistent approach, both to details—such as interfaces—and broader precepts, such as initiatives. This group is completing the collection of data that will allow it to finish guidances in the works.

For more information or to obtain the documents themselves, visit the GHTF online at www.ghtf.org.

—R. DiIulio

Harmonization efforts began with a collaboration between the United States, Canada, the European Union, Australia, and Japan in 1992. The GHTF has been successful in finding consensus among these five member countries and publishing documents containing nonbinding guidelines. However, there is much more to do.

Obstacles have included technical and cultural differences among countries. But the bigger challenge still may lie in a lack of incentive to implement the task force’s recommended guidelines. Without legislation to back the organization’s recommendations, manufacturers and other affected parties are reluctant to put resources behind them. “Without laws, companies are not convinced that changes are final and there is a long-term commitment behind new guidelines,” says Gregory V. Page, PhD, FDA life sciences practice leader at Deloitte Enterprise Risk Services (New York).

The Different Parts

Presently, companies are used to the multiple regulatory processes. “The industry has been dealing with [differences in international regulations] for years, and people know their way around,” Page says.

Manufacturing companies build the regulatory-approval process into product development, starting early and creating timetables for approvals and launches throughout the globe.1,2 These plans take into account the different requirements of each country.

“Because the industry is so pervasively regulated, there are many areas where countries can differ, and these differences can cause significant problems. To the extent that there is agreement among international regulations, there are fewer requirements to meet,” Reichertz says. He notes that differences exist among nations regarding what kind of evidence needs to be shown, how to comply with quality systems and manufacturing practices, even how to set expiration dates.

To achieve harmonization in these areas, five Study Groups—comprised of representatives from each region—complete the research and recommendations. (See “Synchronize Your Regulations” at right for complete Study Group details.) Fred Halverson is VP of corporate regulatory strategy with Medtronic Inc (Minneapolis) as well as a member of the GHTF Study Group 1. Halverson says that not only are there differences in the requirements themselves, but also in the way that they are applied or enforced. “Sometimes, a regulator will use the same requirements but review the data in a different way, or require different data or more data. Or the regulatory organization does not have the resources to look at the data, so perhaps they are trying to do too much with their limited resources,” Halverson explains.

“These systems can?t be changed just because we ‘feel like it.? The law does not allow that. It?s very prescriptive in terms of medical events, so trying to harmonize among nations with different laws is difficult.” ?Larry Kessler, ScD
FDA?s Center for Devices and Radiological Health

The differences mean it takes longer to get things through to market and that manufacturers have to prepare different dossiers for each country. “This takes a lot of extra work and time,” he says.

The goal of harmonization is for companies to be able to prepare one file for all nations. “Because the manufacturer has only one set of data, everybody is basically looking at the same information anyway,” Halverson says, adding that the data must be formatted and presented to meet differing regulatory requirements.

Overcoming Discord

Conformity among the nations of the world is as difficult as it would seem. “The five founding members [of the GHTF] have systems that have been established for a while, so changing them will take time,” Halverson notes. “We are now using the term ‘convergence’ for this process.”

“There needs to be consensus among all members. Science takes a while, and each nation has its own issues.” ?Peter Pitts
Center for Medicine in the Public Interest, former associate commissioner of the FDA

Peter Pitts, director of the Center for Medicine in the Public Interest (New York) and former associate commissioner of the FDA, notes that harmonization efforts require unanimity. No one party can dictate policy. “There needs to be consensus among all members. Science takes a while, and each nation has its own issues,” Pitts says.

This has complicated matters a bit for the GHTF. The group has expanded its scope beyond that of the original five members, working with such other countries as Luxembourg, as well as the Asia Harmonization Working Party and the Latin America Working Party, according to the FDA’s Kessler. At the time of the GHTF’s foundation, there were countries that did not have regulatory systems in place. “There was nothing to harmonize. Over time, more countries have become interested in participating. So there are issues for the five founders and then for others who are ‘sort of’ at the table,” Kessler explains.

“Different countries have different tolerances for risk and benefit, as well as who they?ll let handle it. The European model sees only postmarket problems. The premarket work is done by contractors called Notified Bodies.” ?Fred Halverson
Medtronic Inc and member of GHTF Study Group 1

Some of these participants include countries that did not previously have regulations and are adopting the GHTF guidelines, in full or in part, that are output by the GHTF Study Groups. “We hope, through the GHTF, to encourage these countries to write laws and regulations that mimic GHTF guidelines so we won’t have to go back later and ask them to change,” Halverson says.

Nontechnical obstacles exist as well, particularly cultural attitudes toward risk and benefit. “Different countries have different tolerances for risk and benefit, as well as who they’ll let handle it,” Halverson says, providing an example: “In the European model, the Ministries of Health see postmarket data only. The premarket work is done by contractors called Notified Bodies.”

He explains that with the current European Union model, Company XYZ goes to the Notified Body, which is paid by Company XYZ. Then, Company XYZ has the Notified Body inspect its manufacturing plant and then may affix the CE mark and market its product. “This might not be so comfortable in other cultures,” he says. “In the United States, for example, the FDA looks at and reviews particularly high-risk products and wouldn’t want companies paying for a review. The distinction is not quite as sharp as it used to be, however, with the FDA now charging fees and allowing third-party reviews.”

Moving Ahead without a Head
The FDA has been seeking a permanent commissioner since Mark B. McClellan, MD, PhD, left the organization in March 2004. Lester M. Crawford, DVM, PhD, filled the position officially for 2 months from July to September 2005 (though he had served as acting commissioner prior to that), but then announced his resignation. Currently, Andrew C. von Eschenbach, MD, is acting commissioner, a position he holds concurrently with his role as director of the National Cancer Institute, which he assumed in January 2002.

The FDA has come under criticism for safety issues as well as its handling of the emergency contraceptive drug Plan B. As a result, some expect the position to be open for some time. What does this mean for the agency?

“Commissioners can have some effect on the agency, but in the long run, it doesn’t make much difference,” says Peter S. Reichertz, Esq, an attorney with Sheppard Mullin Richter & Hampton LLP (Washington, DC). Another source, wishing to remain anonymous, commented that at this point, the FDA is larger than one person.

Safety Is Still Job One

No matter who is at the top, the agency will continue to deal with the issues it faces; safety is still a primary concern, particularly postmarket. Many are questioning the role of the organization in this type of surveillance.

According to Gregory V. Page, PhD, FDA life sciences practice leader at Deloitte Enterprise Risk Services (New York), “Postmarket surveillance is an area that, if not of growing concern, needs more work than traditionally has been done in the past. Postmarketing studies generally come about with an adverse event. We may need to change plans to study a product after its release or monitor its performance,” Page says. In terms of harmonization, this work falls into Study Group 2. (See “Synchronize Your Regulations“)

Reichertz expects that regulations in this area will be passed eventually, particularly following the Bausch and Lomb saline recall and stent problems that have been reported. “I see potential legislation in this area, but I don’t expect to see anything soon that deal with speedier approvals,” Reichertz says.

The agency has been dealing with the issue of slow processes itself and has made some progress. User fees and third-party reviews have helped to speed approvals in some instances. “These strategies have been in effect for drug approvals for 10 years, and those reviews have been sped up tremendously. The medical device changes have not been in effect as long and need to catch up,” Reichertz advises.

In the meantime, manufacturers should continue to develop their regulatory and marketing strategies with an eye on the FDA. Even though who’s at the top might not be cause for concern, new rules are.

—R. DiIulio

Kessler notes that the Study Groups are focusing on finding common denominators that will require only occasional changes in laws and regulations. “Most is being accomplished by guidance,” he says.

Getting the Right Key

The problem is that the industry is cautious about putting resources behind guidances that are not guaranteed to become law. “The industry needs to be told that this is what we are going to do, and then they will react to it. People are reluctant to change until they get definite direction,” Page says.

However, implementation of guidances now could help to pass legislation. “The more people who adopt a practice, the easier the legislation is to pass,” says Joseph Vinhais, RAC, vice president of regulatory compliance for Brooks Software (Chelmsford, Mass). “If it is established as a norm, and you can show that it works and incorporates best practices, then you can rebut naysayers. But if there are more people against it who are not performing the practice, then there is more opportunity to challenge it.”

However, Vinhais doesn’t see any reason not to support harmonization. “In order to survive in this world today, companies must be global and flexible. You could end up manufacturing anywhere in the world, and you don’t want to be bogged down with different QMS [quality management systems] or regulations. It would be great to have one set of requirements across the board,” he says.

Reichertz concurs, adding, “The industry is certainly behind it, because it makes it easier to comply if companies have one set of rules. I expect to see more people developing an application that they can use in more than one jurisdiction.”

Closer to Harmony

According to Halverson, the use of international standards is spreading. “The five founding members of the GHTF have recognized many of the same standards, and their use has expanded outside of these five countries,” he says. “A significant accomplishment is the global acceptance of the Quality Management Systems Standard ISO 13485, which is the foundation standard for any regulatory system.”

“The industry needs to be told that this is what we are going to do, and then they will react to it. People are reluctant to change until they get definite direction.” ?Gregory V. Page, PhD
Deloitte Enterprise Risk Services

But there is still more to be done. “The GHTF has written a lot of guidances that will help, but now we need to get them into more use,” Halverson says. He also advocates more training for developing countries to encourage their continued participation. The GHTF conducted training in Thailand last year and Chile this summer; Halverson’s Study Group aims to produce a guidance for nonfounding members that will provide a reasonable pathway for regulation.

All five Study Groups continue to publish guidances. According to Halverson, the GHTF to-do list includes:

  • finish guidances on combination or hybrid products, which, Halverson notes, continue to increase in number;
  • finish Study Group 5 guidances on the handling of clinical evidence;
  • development of a common approach for assessing clinical evidence; and
  • creation of methods for new regulators to increase their participation in the harmonization process.

There is no time line for completion; the process is open-ended. Halverson believes that the GHTF will be working for at least another decade. “We’ve been at it for 15 years,” Halverson notes. “It takes time to organize and get people working together. But we are at a point where we can make more progress. Still, it could take a long time.”

Renee DiIulio is a contributing writer for Medical Imaging.

References

1. Davis W. Not yet approved! Med Imaging. 2005;20(8):33?36. Available at: www.medicalimagingmag.com/issues/articles/2005-08_03.asp. Accessed July 19, 2006.

2. DiIulio R. Not yet approved. Med Imaging. 2004;19(9):40?46. Available at: www.medicalimagingmag.com/issues/articles/2004-09_03.asp. Accessed July 19, 2006.