Have notoriously long review times for device regulatory approval in Japan improved in recent years? An expert on the Japanese device market analyzes the evidence in this two-part series.

Keisuke Suzuki

Japan has jokingly been referred to as the last country to gain regulatory approval for medical devices, excluding North Korea. The Japanese government has been working diligently for more than a decade to reverse this last country mentality and to restore their reputation as the second largest medical device market in the world. The government has already revised the regulations a couple times, established the Pharmaceutical and Medical Device Agency (PMDA) as a separate body from the Ministry of Health, Labour and Welfare (MHLW), and hired more reviewers. The government also implemented preconsultations, much like FDA, but with a fee.  

In addition, the Japanese review process has been divided into three tracks: Equivalent (Kohatsu), Improved (Kairyo), and Novel (Shin). "Equivalent" is similar to CE Mark, with review by a third-party notified body if there is a certification guidance; this is intended to allow PMDA to focus on higher-risk devices. The government has even introduced its "Unmet Clinical Need Device Program," also known as the Device Lag Program, to accelerate the introduction of clinically necessary devices. There are incentives provided, both as expedited review and additional reimbursement, for those who apply earlier or in parallel with FDA.

PMDA claims that its review speed has been neck-and-neck with FDA for "Novel" medical devices since 2009 and that companies are now applying within 1.2 years of FDA. The definition of a "Novel" medical device is "a device in which the design, intended use, efficacy, effectiveness, indication, or performance is not equivalent and differs from what is already approved or certified." This also includes devices which are equivalent to those already approved as "Novel" devices, but the approved device is still under the conditional approval period and has not been granted full approval status.

This finding is auspicious, but there is little publicly available data that we can use to verify this claim. I have read many articles citing this PMDA finding, but none have completed in-depth analyses. As a consultant focused on helping medical devices companies enter Japan, I wanted to verify if this claim, since I have not yet seen evidence of it in my own daily activities. I took the liberty of building my own Excel database to verify if the PMDA claim is valid and to shed some light on the regulatory approval process for those considering entering the Japanese market.

The intent of my research was to examine device lag, which consists of two components: review lag and apply lag. Review lag will determine whether PMDA is slower than FDA to approve new unique medical devices or not. Apply lag is the difference in the speed of availability of new medical devices between Japan and the United States.

Method

PMDA does have a website in Japanese where one can extract information on approved "Novel" and "Improved" medical devices for each fiscal year (April to March). Table 1 shows this data. However, this study has not used this database, but rather extracted data from a paid web service provided by the Japan Association for the Advancement of Medical Equipment (JAAME). JAAME database includes the PMDA dataset, but also provides easy access to all medical device approvals/certifications, the tempubunsho (package insert), risk classification, and the foreign manufacturer name, if any, necessary for completing the database. Also, the FDA medical device database has been used to extract data from those products approved in Japan for those data not available in JAAME or PMDA databases, such as date of submission, type of approval/clearance (510(k), PMA, HDE) and the English product name.

I've constructed three different databases for this analysis--one for "Novel" medical devices, another for "Improved" medical devices, and a third for PMA originals. This analysis considered only original approvals, excluding amendments or supplements. "Novel" devices exempted from being conditional approval were captured but omitted from the analysis. "Novel" and PMA original data between January 2005 and December 2016 was analyzed. Data on "Improved" devices was gathered starting in April 2007, when this track became available.

I analyzed the data from different angles to evaluate if the device lag has improved over the years as PMDA claims. Also, I examined well-worn theories about the Japanese device regulatory process. These include beliefs that a Japanese company can gain approval more easily, that a Japanese clinical study is necessary to gain approval in a reasonable timeframe, and that applications by a distributor are preferred over a manufacturer applying directly. This analysis will shed some lights on the truth behind these beliefs and provide readers with facts derived from the analysis.

Results

Table 1 shows the total number of original approvals for both PMDA and FDA. The term "redundancy" refers to approvals of the same product family on the same day, such as pacemakers or a system consisting of a controller and a catheter that require separate approvals due to Japanese regulations. Pseudo-Novel is those products identified as Novel just because the first product approved with the same nomenclature is still under conditional approval. This analysis omits Redundancy and Pseudo-Novel devices to mimic conditions similar to the original PMA approvals. PMA approvals for IVDs were also excluded from the analysis, as the Japanese database has not accounted for them. IVD was included in the drug category until recently.  

Graph 1 shows the number of approvals in chronological order. PMDA has been approving about 10 Novel devices and 30 Improved devices annually, compared to 23 PMA original approvals by FDA. In 2016, FDA approved 933 PMA supplements, including IVDs, whereas the PMDA approved only 9 Novel amendments and 8 Improved amendments. This difference suggests that either there is a significant difference between a supplement and an amendment, or a supplement by FDA and Improved by PMDA are equivalent, as the definition of Improved is those that are not Novel or Equivalent.

Graph 2 depicts the chronological average review speed, with the trend showing that PMDA has improved its approval speed to a level competitive with that of FDA. The trend line for PMA devices is quite flat, whereas, for Novel devices, it is trending steeply downward. This means that it has improved over the years, with a turning point around 2013. If PMDA continues this trend, there is potential for the PMDA review speed for Novel devices to outpace FDA review times for PMA original submissions. The paired t-test on 2016 data shows that there is no significant difference between PMDA and FDA on approval speeds, though the average speed shows that PMA (483 days) was faster than Novel (650 days) or Improved (624 days). Surprisingly, in 2015, PMDA review of Novel devices was significantly faster than FDA for PMA. In 2014, there wasn't statistical significance among the data. In 2013, the FDA review time was significantly longer than PMDA review times for both Novel and Improved devices. 

Drawing on this analysis, it is fair to say that the PMDA review time for Novel and Improved devices is now as fast as FDA review times for PMA original submissions. This result confirms that PMDA has drastically improved its speed of approval for Novel and Improved devices and is competitive or even faster than the FDA on PMA original submissions.

Based on the above result, we have limited the data to only the last five years, beginning in 2012, because of the acceleration in PMDA approval speed shown in Graph 2. Interestingly, Table 2 shows that the average FDA approval speed is slower than PMDA. There is no statistically significant difference in approval speeds between the three groups. 

Table 3 shows the same data for the whole period, beginning in 2005. This shows a different picture, but the maximum review time is still high for all three groups. This means that if a regulatory application that does not meet the regulatory body standards and expectations is submitted, it will take a long time to gain approval. 

To gain meaningful insights, the rest of this analysis will only focus on data from 2012 onward. However, it's worth noting that the data does not account for the time spent during the paid consultation process, which might have influenced the PMDA outcomes. PMDA performs an extensive review during these consultations, ensuring value for the fees paid and reducing the incidence of low-quality submissions that could impact overall approval speeds. Based on PMDA presentations, the body performs about 160-170 paid consultations annually. This means more than half of the submissions are likely going through this paid consultation process.

My remaining findings will be explored in Part 2, to be published later this week. Stay tuned for more on the truth behind common beliefs about the Japanese regulatory approval process and a better understanding of the PMDA apply lag.

Keisuke Suzuki is the consultant and owner of Keisuke Med Tech Consulting LLC. Reach him at [email protected].

[Image courtesy of DOMDEEN/FREEDIGITALPHOTOS.NET]