Convergence: How to navigate the US-Japan 'Harmonization by Doing' program
Regulators from the US Food and Drug Administration (FDA) and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) discussed how medical device sponsors can get approval for global studies accepted into the regulators’ joint “harmonization by doing” (HBD) program.The program is designed to save development time and costs in developing life-saving cardiovascular devices through the simultaneous review of global studies, explained Shin Iwamoto, a PMDA principal reviewer, at RAPS Convergence 2021, held virtually on 13 September.
The HBD program was established by regulators in 2003 to seek regulatory convergence in premarket review of ‘breakthrough” medical devices in cardiovascular technologies (RELATED: Summary Technical Documentation (STED): Harmonizing a predictable regulatory submission, Regulatory Focus 26 September 2013)
The program was designed to target a lag between the time devices are approved and introduced into the US market and when approval occurrs in Japan, with resulting delay in patient access to new medical technology, explained PMDA officials at a HBD think tank meeting in 2017.
In one HBD effort, a joint US-Japanese workgroup is working toward developing cardiovascular devices with a single global clinical trial protocol rather than with separate country-specific protocols.
Some examples of products approved by FDA and PMDA via the HBD pathway include:
- Cook Ireland’s Zilver PTX drug-eluding peripheral stent, approved in November 2012
- Terumo Medical Corporation’s Misago peripheral elf-expanding stent system, approved in May 2015
- Cardiovascular Systems’ orbital atherectomy system (OAS), approved in March 2017
- Medtronic’s Harmony Transcatheter pulmonary valve, approved in March 2021
Meet with regulators early
Kenneth Cavanaugh, the deputy director of FDA’s Office of Cardiovascular Devices in the Center for Devices and Radiological Health (CDRH) suggested sponsors who are interested in participating in the program need to consider how global trials are different, and how these differences will affect the US population.
Some potential differences include the level of physician experience, patient characteristics, and patient and physician attitudes toward clinical studies. Additionally, sponsors considering a global trial should consider clinical site infrastructure and monitoring, the quality and reliability of the collected data and the standard of care, and how device reimbursement may vary from country to country.
Cavanaugh said that sponsors who are interested in the HBD program should meet with FDA as early as possible in a presubmission meeting to get feedback on a possible submission and to get input on the data collection. Cavanaugh pointed out that there no fees involved in presubmission meetings.
If sponsors decide to go through with a global study after these meetings, they should reach out early to regulators and not wait in their regulatory interactions. “Course corrections become more challenging to implement in later stages of development,” noted Cavanaugh.
Cavanaugh also suggested not limiting discussions to premarket studies, but to include post-market surveillance in the discussions as well. “This can present a valuable opportunity for global evidence collection and use.”
He also urged sponsors to be upfront about non-US aspects of the clinical and regulatory strategy. “Don’t assume FDA won’t care about clinical evidence or plans involving other countries.”
Iwamoto of PMDA concurred with his colleague that early interaction is important. He also advised sponsors to “carefully consider” the feedback they receive.
Understand regulatory differences
Neal Fearnot, president of Cook Advanced Technologies and President of MED Institute Incorporated, also offered some industry advice on conducting clinical trials through the program.
One tip: sponsors should understand some of the challenges in conducting early clinical studies when regulators’ approaches may differ. In the US, reviewers assess the safety and adequacy of these studies in an investigational device application while in Japan, one review division reviews safety and another department reviews adequacy.
He also reiterated his colleagues’ point to “consult early and often with PMDA and FDA.”
Fearnot also advised companies to “align company resources to manage a simultaneous clinical trial.” This includes providing adequate in-house resources to staff parallel programs by assigning top engineers and technical staff to manage the project and enabling close communication between US and Japan project teams through regular calls and meetings.
Developers should also be sure to comply with both Japanese and US Good Clinical Practices (GCPs) at all sites.
Fearnot identified a key lesson learned from their participation in the HBD program: “The quality of the data from Japan was at least as good as the quality of data from the US.”
Another surprise, he said, was that “the approval was actually quicker” in Japan for one of the company’s applications submitted through the program.
RAPS 2021 Convergence
