Medical Device Daily Washington Editor

The Global Harmonization Task Force (GHTF) is forging ahead to standardize at least some aspects of international medical device regulations, and FDA and Japan's Ministry of Health, Labour, and Welfare (MHLW) have undertaken an effort to align specific elements of the way that medical devices come to market in each of those nations.

The effort, known as "Harmonization by Doing" (HBD), could make it easier for sponsors to roll out trials that will win the product a place in both markets through one clinical trial. But as always, the details potentially contain some devilish hang-ups.

According to the FDA statement, HBD is "an international effort to develop global clinical trials and address regulatory barriers that may be impediments to timely device approvals." Informally launched in 2003, HBD is geared not toward a "theoretical approach to harmonization" but is structured to "utilize parallel development, application submissions and review of actual medical device projects by FDA and MHLW-PMDA" — the acronym standing for the MHLW's Pharmaceutical and Medical Devices Agency.

With the help of organizations such as the Duke Clinical Research Institute (DCRI; Durham, North Carolina) and members of academe and industry from both nations, HBD is attempting to "eliminate redundancies, added costs and time delays inherent in sequential trials."

The organizers are interested in developing "common protocols for investigational clinical studies that would allow safe and effective 'breakthrough' cardiovascular technologies to benefit patients worldwide," and the concept "can be broadened in scope beyond premarket activities" to include post-market studies and patient registries.

Over time, the organizers hope that the process will prove itself and be applied to "other medical devices, such as orthopedic products and others." Similar relationships with "other regulatory bodies can also be developed in the future," although apparently no other such efforts are underway.

The HBD concept took seed in 1993 when Mitchell Krucoff, MD, director of DCRI, led a team of regulators and researchers in a harmonization effort known as "Heart Knows No Borders." The group met regularly enough to keep the ball rolling, and HBD was first announced as an official effort during a 2004 meeting of the Japanese Circulatory Society (Kyoto).

The organizers followed with a "think tank" session the following year.

At present, HBD is organized into tasks undertaken by four working groups (WGs). The global cardiovascular devices trials WG will take a crack at the "operational and regulatory challenges to executing single clinical protocols for device evaluation in Japan and the U.S." Among the topics this WG will tackle are data pools, multi-national randomization and integrated submission strategies.

Other WGs will work on post-market registries, clinical research infrastructure and regulatory convergence. This last group will take aim at "translation of good clinical practice regulations," and will examine the use of GHTF document formats.

Susan Alpert, MD, VP of quality and regulatory affairs at Medtronic (Minneapolis), told Medical Device Daily that the HBD and GHTF efforts are more or less complementary. "The issue is that GHTF sets standards and approaches but isn't structured in a way that allows for real pilot project work," she said.

Japan seemed a logical partner for the HBD approach because "Japan was not doing a lot of clinical work in the device arena."

Some devices have to be sized differently for some Asian populations as compared to the U.S., a situation that Alpert said "is true for almost everything." But that fact does not have to drive a substantially larger enrollment in device trials.

For stents, "the goal is to have enough availability of smaller sizes" to satisfy Japan's regulators, she said, but the extremes in the range of physical size are not always an issue so long as subjects of a more typical anatomical configuration are sufficiently represented.

Japan's incentive for participating in this effort stems partly from its absence of a strong infrastructure for the conduct of clinical trials.

Regarding physicians, Alpert said that Japan's doctors receive superb training in the country's medical schools. But as to clinical investigation, "they have some who are qualified" but must get more doctors up to speed on the ins and outs of clinical investigations.

"They don't have the rest of the infrastructure," either, she noted, and medical centers in Japan also must get up to speed on management of study articles, patients and data. She said that the government "is very dedicated to growing that capacity."

FDA has expressed some interest in adaptive trial designs despite the fact that such changes have riled FDA reviewers. But the question is even less certain for Japan's authorities.

Alpert said she is "not sure if they have experience with adaptive design because they're still developing standard randomized controlled trials."

Japan's stock of statisticians is certainly up to the task of sorting out the mathematical problems that come with adaptive trials, but she said trials will depend "on the commitment of companies and physicians to work in that environment," given the uncertainty as to how such a trial might be received by the PMDA reviewers.

Working on a more or less parallel track, the Global Harmonization Task Force (GHTF) recently released a recommended set of rules for a summary technical document (STED) that would provide a baseline of information in a standard format for all regulatory bodies that sign on to the GHTF.

The document states that the guidance would not apply to devices "used for the in vitro examination of specimens derived from the human body" but would provide data on design and manufacturing information, product validation, sterilization, biocompatibility, and animal studies data for almost all other medical devices.

The document notes that "there is no specific advice on device-medicinal combination products but it is anticipated that the GHTF will develop recommendations in the future."

GHTF will meet in Washington in early October, with its agenda including discussions of nanotechnology, biomarkers, clinical trials in nations with no regulatory bodies and quality systems audits for multiple regulatory agencies.