Last Updated on 2023年3月16日

Hello, in this article, I’ll introduce the regulatory affairs (RA) regarding ethical drugs, classified as First-class marketing license in Japan. I think that the basic work contents are equally applicable to regulatory affairs other than ethical drugs. This time, I’ll explain roughly what kind of work dividing it into regulatory affairs positions on career change sites or job vacancy information, and also the relationship between each.

Regulatory affairs for ethical drugs / Pharmaceuticals in First-class marketing license

When I think about what regulatory affairs are, I can’t give a general answer, but when I was engaged in clinical development, I imagined the following tasks of regulatory affairs.

Submit regulatory documents and apply to obtain the approval
Consult with PMDA
Coordinate not only clinical development but also other departments such as manufacturing and sales

When I was actually engaged in RA (in Japan), there were things that were as I had originally imagined, but there were also parts that weren’t. A particularly interesting point is that the scope of regulatory affairs differs from company to company. Unlike MRs, regulatory affair’s staff doesn’t require certification, nor does it require license to practice pharmacy. Therefore, I believe that there is no clear line to be drawn in regulatory affairs. For example, if you are a major company, there are many products and items, and they need to subdivide a huge amount of work, so everyone would agree that the number of positions will increase. In small and medium-sized companies, while there are few products and items, it is expected that each person in charge of regulatory affairs will be responsible for a wide range of duties. On the other hand, apart from the size of the company, there is also a difference in which department undertakes new-drug application (NDA) and the strategy. For example, in a company, the clinical development department is responsible for NDA and the strategy. Therefore, I believe that if there is a person in charge who has mastered procedures related to regulatory affairs and has the ability to respond, there is no need to be a regulatory affairs department. In practice, concentrating too much work on a specific person, is not recommended.

Types of RA

RA’s positions (for ethical drugs / Pharmaceuticals in First-class marketing license) seem to be recruited for the following five categories. In particular, R&D (or just RA ), Post-marketing (lifecycle maintenance and compliance), and (R&D) CMC are typical three regulatory affair’s positions. However, depending on the size of the company and the items handled, positions may be added, or conversely, they may be combined into one position. I will mention about each position on the premise that the number and groupings differ depending on the company.

R&D RA

R&D RA works for the first and most important phase ‘apply – Obtain the approval’ before the life cycle of pharmaceuticals is created. R&D RA is recruited by companies handling new drugs, and in many cases, the following knowledge and experience are required in Japan.

Plan (regulatory) timeline and strategy leading up to approval of the NDA in Japan
Correspond and negotiate with PMDA (and Ministry of Health, Labor and Welfare)
Prepare of regulatory dossier/documents (CTD, etc.)
Keep up to the date with Japanese procedural requirements and regulation (Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices, and related laws and regulations)
English (to communicate with the foreign company or global colleagues)

In all job descriptions, relatively similar content is written, but experience and knowledge are required at a high level for the items or areas that each company is developing, and it takes a long time to accumulate experience until the RA can handle them responsibly. In addition to the above, the RA may also be required to be responsible for drafting package inserts, applying for certification as a foreign manufacturer accreditation, and completing procedures for NHI drug price listing. In large companies, each role has its own person in charge. In the process of putting together the regulatory documents for NDA, RA often review and organize them, and it is necessary to monitor whether the act and the related laws are complied with. As a result, a wide range of knowledge is required, including safety, pharmacokinetics, and overseas usage, and cooperation with other departments is strongly required.

The knowledge and experience listed above correspond to the advanced items in order from the top. In addition to planning strategies, important tasks in R&D RAs are dealing with and negotiating with PMDA (and the Ministry of Health, Labor and Welfare). Regarding correspondence and negotiations with PMDA (and the Ministry of Health, Labor and Welfare), R&D RAs will answer inquiries and explain and prove the propriety and/or compliance of quality, efficacy and safety. In a limited amount of time, R&D RAs are required to organize a huge amount of information and deal with the points and doubts of PMDA (and the Ministry of Health, Labor and Welfare) with flexible thinking. Especially with new drugs, unexpected situations can occur, so it is necessary to work with other departments to find the best possible response.

Post-marketing RA

Post-marketing RAs have a wider range of duties than other RA positions.

First, Post-marketing RAs mainly deal with products on the market after obtaining approval (In some companies, Post-marketing RAs seem to deal with also new drug approval applications). Specifically, Post-marketing RAs are in charge of change managing (minor change notification, partial change approval application, etc.) related to approval application forms that have been approved. There can be planned changes and sudden changes, so it is necessary not only to make a plan, but also to monitor in advance so as not to miss any sudden changes. Since Each pharmaceutical company is responsible for managing all pharmaceuticals on the market, the more products on the market, the more work. Since change management involves various changes related to the manufacturing site, such as manufacturing method/process changes and test method changes, Post-marketing RAs often work with CMC RA and Quality Control/Quality Assurance Department regarding GMP compliance inspection following Partial change approval application.

Secondly, Post-marketing RAs are responsible for managing business license, etc, such as marketing, manufacturing, and wholesale distribution. The licenses are required to be updated regularly and the quantity is large. I don’t think it’s unlikely, but if the licenses are not updated, the business will be forbidden, so managing business licenses requires a big responsibility. In addition, Post-marketing RAs may be required to be responsible for responding to GMP compliance inspections as a staff of the company’s Quality Assurance Department.

The third is regulatory reveiwing and support for advertising and promotion. Those activities and materials must be ensured with regulatory compliance.

In addition to the above wide range of duties, they may also be responsible for creating labeling and package inserts. Therefore, I think that the scope of Post-marketing RAs varies greatly depending on the company.

CMC RA

Compared to R&D RAs and Post marketing RAs mentioned above, CMC RAs are more closely related to manufacturing and quality. CMC RAs may belong to a department related to CMC, a factory or a research center instead of the RA department. CMC stands for “Chemistry,” “Manufacturing,” and “Control.” CMC RAs handle Manufacturing process of active pharmaceutical ingredients and products, manufacturing procedure, specification and testing method, stability, physicochemical characterization, batch analysis, then they integrate to CTD and the application form as data or documents. Many active pharmaceutical ingredients are manufactured overseas, so it is necessary to translate documents and reports, and to confirm and respond to whether the documents and data meet the requirements for Japanese regulations. Since CMC RAs are related to manufacturing, CMC RA’s tasks include PCA, MCN, GMP compliance inspection, Import/export of drug substances and products, and etc, in some cases.

I’m not familiar with CMC RAs well. Through looking at the CMC RA’s recruitment, there are cases where RA experience (not CMC) is written in the qualification for CMC RA. In some pharmaceutical companies, (especially Post-marketing) RA prepare for submitting data and answering to queries from PMDA (and the Ministry of Health, Labor and Welfare) regarding CMC. And (R&D or Post-marketing) RAs have opportunities to learn about the work of CMC through their work. Therefore, even if RAs do not know details about CMC RA at first, I think (R&D or Post-marketing) RAs can gain more or less experience in CMC through tasks of (R&D or Post-marketing) RAs.

Electronic submission / Submission (management)

The position regarding electronic submission management in new drugs is a relatively new position in Japan. In 2003 , Transferring electronic of CTD (Common Technical Documents) for NDI start to be discussed, and PMDA started accepting eCTD since Apr 1, 2005, which is an electronic medium (CD, DVD, etc.) in Japan. From October 1, 2016, it became possible to accept applications to the PMDA through communication from a portal site on the web called Gateway, after repeated improvements and discussions with industries. Until March 31, 2020, as a grace period, PMDA accepted not only electronic media applications, but also direct delivery and mailing of paper media, but from April 1, 2020, only eCTD gateway applications will be accepted in principle. On the other hand, applying to get MA of generic drugs are still mainly submitted by paper CTD.

Electronic submission / Submission management is required to create and convert the CTD to electronic media as eCTD according to the appropriate standards for electronic submission, and to organize it into an appropriate file so that errors do not occur at the time of submission. Not only the eCTD at the time of submission, but also electronic data submission required by PMDA, receipt of inquiries after the submission, responses to inquiries, and resubmission when necessary, will be handled through the gateway.

Electronic submission / Submission management vacancies are available at large companies selling new drugs. This is because it is more efficient for large companies to separate the function/position to deal a lot of pipeline and items requiring electronic submission. Since the amount of work is not large enough for small and medium-sized companies to specialize in, I think that (R&D or Post-market) RA will be responsible for electronic submission / submission management. There are many CROs who are proficient in the field of Electronic submission, and I believe that there are many pharmaceutical companies that rely on the help of CROs. Coordination and management with CRO will also be part of electronic submission / submission management. As a result, it seems that they have set up a separate department from the existing RA department to differentiate themselves.

RA Document and Clinical trial protocol notice staff

This position is described as above because I do not know the distinguishable position name. This is a position (in a broad sense, as a RA) recruited by CRO. As far as I can confirm, I don’t think that the above job offers have been posted by pharmaceutical and medical device companies. Duties include submission of clinical trial notice, creation of informed consent document, support for creation of clinical trial protocol, support for creation of investigator’s brochure, and QC / review of CTD and PMDA consultation materials. There are many supports and QC work, and it is often written as welcoming inexperienced in recruitment.

I think this position is closer to development than RA. First of all, it depends on the company whether the clinical trial notice is submitted by the (clinical) development department or the RA department. Except for the initial submission of the clinical trial notice, most of the information related to medical institutions, support institutions, and investigators in clinical trials is updated, so I do not think that RA necessarily need to respond. it is actually and occasionally not dealt with by RA but clinical development. Next, regarding informed consent document, clinical trial protocol, and investigator’s brochure, judging from the duties of the recruitment, it is considered to be a clinical development work rather than a RA work. On the other hand, PMDA consultation materials and CTD can be said to be RA’s work. However, I’m not sure if the work related to PMDA consultation materials and CTD, which can be said to be RA’s work, is limited to QC and reviews, and whether it will lead to a career path as a RA. As a result, I have the impression that most of the work involved is clinical development rather than RA.

If I have a chance, I would like to gather information of the RA’s work in CRO.

Summary

I have introduced the RA business by dividing it into 5 positions as above. I don’t know yet everything about RA, so the contents of the degree that I saw and heard are also included. Although it is simple, the figure below summarizes which stages each RA is mainly responsible for from the development of ethical drugs to the market in Japan.

Although it is rough, I would appreciate it if I could correctly convey the relationship between RA and the work. As mentioned at the beginning, departments and organizational structures related to RA have different names and categories depending on the company. In the future, I would like to introduce more detailed work related to RA.

No 003: Types and duties of regulatory affairs (ethical drugs / Pharmaceuticals in First-class marketing license) in Japan.