In prior installments of this column, in order to help entrepreneurs in their companies’ early stages look for creative ways to help move programs forward or to provide additional value, we’ve discussed how regional licensing partnerships are an option for non-dilutive financing (financing that doesn’t require the sale of shares of your company). In this month’s column, we’ll focus in on a few considerations related to doing business in Japan. Japan is one of the top markets for ophthalmology products in the world and, in some cases, is the second-largest market behind the United States. As such, it should be an important component in your early global development planning. In other regions such as Europe, Canada or South America, for some programs the clinical package from the U.S. is sufficient for filing, but the considerations for bringing programs to Japan are unique. If you plan to pursue a regulatory meeting in Japan, then, it’s helpful to understand the nuances related to regulatory interactions there. Here, we’ll cover a couple of key highlights related to the early part of the process.
In the past there’s been a considerable time lag between development and approval in the United States and an ultimate launch in Japan. Given the size of the market in Japan, a more global follow-on or even parallel strategy makes sense, and can add more value to your program as you look for partnerships with global companies. In fact, Japan is becoming a market of interest earlier in products’ lifecycles, and it can be very useful to show investors or global partners what a development program looks like in Japan—even if actual clinical development isn’t initiated yet. We’ve seen many companies and entrepreneurs focus solely on Food and Drug Administration interactions through Phases I and II, all the while ignoring other territories. However, investing just a small amount of time and resources in these other regions—including Japan—can yield valuable information on regulatory interactions. A word to the wise, though: If you’re going to invest extra time in Japan, start early, because it may take additional time to gain confirmed written comments.
In Japan, the FDA’s counterpart is known as the Pharmaceutical and Medical Device Agency. In many regards, the PMDA is very similar to the FDA. With some requirements having been harmonized across regions as ICH Guidances (International Council for Harmonization), components such as toxicology and manufacturing generally are consistent and many times don’t require additional work or rework. In some regards, interaction with the PMDA is very similar to dealing with the FDA. One main difference between the two is that, in the initial stages of the process, rather than a single pre-IND meeting with the FDA, working with the PMDA involves a multistep process.
The first interaction with the PMDA is called the jizen mendan (“preliminary meeting”). This meeting has no fee associated with it, is shorter in length and requires less of a briefing package. It’s important to recognize the role of this meeting: You won’t leave with formal written comments from the PMDA and it isn’t intended to discuss details of the development program or clinical protocols. The intention of this meeting is to confirm the materials that are to be submitted and the sponsor’s questions that will be discussed at the subsequent taimen jogen (“full consultation meeting”). Certainly, many times it is natural to wish to obtain as much information as possible during regulatory interactions, but many times we see clients having high expectations for confirming details and answering all questions about a bridging program at this preliminary meeting. However, it’s important to recognize the PMDA review isn’t formalized at this stage and they will not have reviewed all the information and data.
However, this first meeting is still very important for setting the stage and starting a working dialogue, relationship and level of trust with the PMDA. The second meeting, the full consultation meeting, is more similar to a pre-IND meeting with the FDA, in that a more detailed briefing document is submitted in advance and written comments are provided by the PMDA following the meeting. This meeting does carry a fee, which currently is in the range of $50,000. In many instances, additional clarifications are required after this meeting, and the PMDA has always been very helpful and responsive about providing clarifications as needed.
Again, it’s important to recognize that maybe several rounds of meetings might be necessary in order to finalize plans. Companies must recognize that everything won’t be formalized in one meeting during a single trip to Japan. The PMDA is very thoughtful and data-driven and, in some cases, though it may not require preclinical or pharmacology studies to be repeated, it may ask for data to be presented in a different manner to help support such things as drug concentration and dosing selection.
The PMDA also views ethnic differences as very important for interpretation of clinical data. In cases in which pharmacokinetic or pharmacodynamic data is being used, you have to show how the Japanese population compares to the original data set. The PMDA typically wants to see dose ranging established in the Japanese population specifically. This is due to potential differences in both drug activity and dosing frequency, as well as to differences in practice patterns that might relate to whether the drug is used as primary, secondary or objective therapy. For example, drugs in some indications may need to be dosed more frequently in Japan than in United States.
One key point to recognize is that the PMDA has been very open to helping clients run early studies as efficiently as possible, and therefore will generally accept the Phase I/pharmacokinetics being done in the United States, if done in Japanese-American patients. But we do generally see that the PMDA wants a traditional Phase I/PK study to be conducted/repeated as a first step, even in cases where a program may have proceeded directly into Phase II in the United States, or Phase I data already exists, but with a non-Japanese population. This includes situations in which Phase III may already be completed in the United States or the product is commercialized. Similarly, many times Phase II dose ranging may also be done in the United States in Japanese-American patients. However, generally speaking, the confirmatory Phase III is required to be done in Japan.
The safety requirements are specific to the drug’s indication and the amount of data already in hand from other parts of the world. In some cases, the additional safety requirements for a number of patients may be less than the full safety package already completed in the United States, and may even be in the form of an open-label study. The key is that the PMDA is looking for efficacy and safety to be established in Japanese patients. It’s open to reviewing data from subgroups of patients that may be of Japanese descent from the United States to support early data. However, we usually find that the number of Japanese-American patients included in U.S. studies isn’t large enough to eliminate the need for repeating Phase I and II. The PMDA is also very conscious of reducing the timeline of development between the rest of the world and registration in Japan.
In many respects the PMDA will view data in a way similar to the FDA. In some situations, they do have other thresholds. For example, in the case of dry eye, PMDA’s requirement for approval is to demonstrate a statistically significant improvement in one sign only, specifically corneal staining. This is an important nuance, and is slightly different from the FDA in that there are a few products that are approved in Japan that aren’t approved in the United States, namely diquafosol and repabamide. There are also areas of emphasis that the PMDA is keen to address, such as neuroprotection, given the higher incidence of low-tension glaucoma in Japan, and allergies, which are a severe problem there. In these conditions, there may be opportunities for parallel development—or even leading development—in some cases in which it makes sense.
Naturally, this article isn’t intended to be an exhaustive review of regulatory strategy for Japan. However, we hope this discussion at least highlights the importance of looking into the Japanese market for your product, and considering starting an earlier dialogue with the PMDA than you may have originally planned. This will help show potential partners your focus on global development, and there may be opportunities for building and deriving additional value early. For example, some companies may see an opportunity for a potential regional partnership in Japan. We’ll use this primer as a springboard for future columns on global development, including development in China and other Asian countries.
Mr. Chapin is senior vice president of the Corporate Development Group at Ora, Dr. Matsuda is general manager of Ora Japan KK, and Ms. Kawaba is a senior director of Ora Japan KK. Ora provides a comprehensive range of development, clinical-regulatory and product consulting services for developers, investors and buyers; preclinical and turnkey clinical trial services; assistance with regulatory submissions; and the integration of assets, business partnering and financing support in ophthalmology. Ora Japan KK is based in Osaka for local regulatory, clinical operations and business development support. We welcome your product development comments or questions. Please send correspondence to email@example.com or visit oraclinical.com.