By Poonam Balani
This piece represents the views of the author and not necessarily the views of Informa Connect Life Sciences or the Global Pharmaceutical Regulatory Affairs Summit.
Regulatory authorities around the world continue to adopt internationally recognised data standards set by the ICH in an effort to improve the efficiency. The adoption of these standards not only allows individual national authorities to improve their own processes, but also allows for increased cooperation and information sharing among global regulatory authorities. In 2017, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) expanded its membership with the addition of CFDA (China Food and Drug Administration), which has been renamed as NMPA (National Medical Product Administration) effective September 1st 20181 and Brazil’s National Sanitary Surveillance Agency (ANVISA)2.
Harmonised standards facilitate global collaboration of the pharmaceutical developer with regulatory agencies. Submission of applications for the process of market authorisation are efficient when all stakeholders follow similar standards. Therefore, the use of harmonised standards can allow for the reuse of core sections of the regulatory submission content from one country or region to another. eCTD provides many advantages over paper or non-eCTD electronic submissions which include:
The version eCTD v3.2.2 is expected to be upgraded to eCTD v4.0 to facilitate the processing and review of electronic regulatory submissions. eCTD v4.0 is based on the Health Level Seven (HL7) standard which aims to broaden the use of the eCTD format beyond life sciences to be able to support electronic submissions for medical devices and veterinary products among others.
In the EU region, with the EMA headquarters shifted from London to Amsterdam, the timeframe for the implementation of the new standards is expected to be extended beyond 2020/2021, as previously planned in the major world regions [1]. While electronic submission using a common platform such as eCTD certainly makes the review process, the flow and management of information streamlined across regions, it is efficient to use this system only if the industry stakeholders have a global regulatory strategy. What makes a common platform such as eCTD challenging is the differences in the regional requirements, which are justified considering the disease profile, which may be different in different world regions. This may require additional regional guidance for the disease, and therefore a specific indication targeted. Additionally, the product lifecycle follows different paths in different world regions. Nevertheless, the new eCTD v4.0 will incorporate features to accommodate the changes required for the regional sections as well as a two-way communication between the regulatory agencies and the entity filing the application. Several new measures concerning the change management are also expected to improve over the current eCTD version 3.2.2.
Different regional requirements for submissions in different world regions and individual countries present several major challenges in the implementation of eCTD across the regions. New developments and regulatory challenges associated with the submission of applications in Brazil, China, the GCC and Russia are discussed in the following sections.
The Brazilian registration system has regional specifications and similarities with the ICH CTD format. The Brazilian regulation requires that the submission dossier be structured for product registration in two main parts:
As Brazil is an official member of the ICH since November 2016, it has been working towards the process of prioritising and updating the adaptation of the ICH guidelines, including M4: Organization of the Common Technical Document for the Registration of Pharmaceuticals for Human Use. However, a document similar to the Section 2.3 of ICH CTD (Quality Overall Summary) is not required for Brazil but there is a mandatory requirement for the clinical and non-clinical summaries and overviews corresponding to the Modules 2.4 through 2.7 of the ICH CTD.
While the ICH guidelines on safety and efficacy of drug products are accepted in Brazil, the quality section of the Brazilian dossier represents a major challenge when planning a global submission strategy as it has several differences in comparison to the ICH CTD format along with the requirement of GMP certificate issued by ANVISA. Additionally, safety and efficacy reports have to be submitted along with Modules 4 and 5 of the ICH CTD. As a member of the ICH, ANVISA must implement the ICH M8 guideline regarding the electronic Common Technical Dossier (CTD) in Brazil until December 2023 [2].
Current regulatory procedures where electronic submissions are not allowed require documentation to be submitted in paper and in person, directly to ANVISA. Moreover, official documents issued by other health authorities in foreign languages, that are submitted for registration purposes in Brazil must be accompanied by a certified translation conforming to the legal requirements in Brazil, which is a time-consuming process and brings additional costs for the applicant. The requirement for submission of bilingual dossiers in Portuguese and English not only increases the total documentation load that needs to be prepared, but is also cumbersome where archiving and change management is concerned. For a new registration, many administrative documents such as the application form, the Certificate of Pharmaceutical Product (CPP) and GMP certificates have to be submitted in the official language Portuguese.
It is important to have sufficient expertise with the local procedures and possibly engage early with local consultants for successfully making regulatory submissions in Brazil. Currently, ANVISA’s website is presented in two languages: Portuguese and English. However, the English version is limited in contents and lacks complete information which is only accessible in the Portuguese version [3].
China has focused on pharmaceutical development and in order to expedite the review and approval of new medicines, China is expected to conform to the eCTD format for accepting submissions in near future. As China is now a member of the ICH (International Conference on Harmonisation) since June 2017, the draft eCTD guidance has now been detailed by the NMPA(National Medical Product Administration, formerly CFDA). The NMPA will conform to the eCTD version 3.2.2, which is close to the US FDA’s submission process and the format will require clinical trial datasets and Study Tagging Files (STF). It is currently in the stage of being implemented and the submission will be required both in Mandarin and English language for reference purposes. Initially, it is expected that the submissions will be allowed through CD/DVD initially and later a switch will be made to the usage of an electronic gateway.
One of the key challenges with the electronic submissions for the Chinese market involve the requirement for the usage and handling of multi-byte Chinese character sets. Most often, local tools are used to ensure the converted content meets the local technical submission guidelines. The industry stakeholders have to ensure that all supporting content creation, management, manipulation, publishing and validation technologies support the multi-byte Chinese documents which will be used.
Secondly, understanding the differences in the cultural requirements and interpretation of technical requirements laid down by the guidelines would be essential to use the electronic submission strategy for the Chinese market. To this end, partnering with an enterprise/service provider with excellent understanding of the local regulatory requirements is expected to be imperative for successful submissions and market authorisations. Training the regulatory personnel for eCTD submissions can also be of significant benefit to the pharma companies’ involvement in any governmental pilot projects that would be used to test the electronic platforms for submission, and can give an upper edge to the pharmaceutical companies in preparing them for the future use of fully electronic submissions.
Since the initial release will not mandate the use of eCTD, this transition period provides biopharmaceutical companies with the opportunity to avoid the pitfalls experienced while adapting the submission process for other regions. Supporting technologies have also evolved since eCTD was first introduced to the global stage, which could also be leveraged by the pharmaceutical companies to their benefit while making marketing authorisation submissions in the Chinese market.
The GCC includes Saudi Arabia, Kuwait, Oman, United Arab Emirates, Bahrain and Qatar.
While Saudi Arabia and Bahrain require eCTD submissions via electronic portals since 2015, other GCC countries lag behind in this aspect. The GCC has also worked on the process of a centralised submission of documents for marketing authorisation, which can be submitted to the Gulf Central Committee for Drug Registration (GCC-DR) and an approval can allow the medicinal product to be marketed in all Gulf countries. The challenges in the GCC countries include the specific local administrative requirement for each country (Module 1 in the CTD format). Other than that, there is a specific requirement for documents for the GCC countries, which can prolong the submission times while adding up extra costs include:
Other than that, there are legal requirements for labelling for each country and a copy of reference pharmacopoeia is required at the time of drug registration, except for Bahrain and Oman. The product leaflet needs to be provided in Arabic and English language along with other registration documents.
The CTD format is mandatory for submission of marketing applications in Russia since July 2015 and it is possible to submit applications electronically after a registration process and obtaining a password from the state website, which has largely helped in increasing the transparency of the process of authorisation. The Russian federation has adapted a development strategy for the pharmaceutical industry with an aim to replace the import of 90% of the medicinal products included in the list of essential drugs by domestic production until the year 2020. This is to achieve an innovative model of development for the pharmaceutical industry in the Russian Federation and to increase the competitiveness. One of the key steps that will be undertaken include the process of harmonisation of the national standards with international best practice and to promote technological advancement of the Russian pharmaceutical industry.
Russia does not recognise GMP certificates issued by regulatory authorities of other countries and requires local GMP certificates for foreign producers since January 2016, which have to be included in the marketing authorisation application [4], and for other regulatory actions, such as authorisation renewals and variations. The GMP inspection procedure in Russia is long and the inspection capacity constraints have been aggravated by the lack of a provision for the transition period, hindering the access of foreign producers to the Russian market.
While the registration dossier for the submission of marketing authorisation application in Russia is very similar to the EU dossier, the language of submission is Russian and the stability data in Russia is required for climactic zones I and II. Other specific regulatory requirements as well as the ever-changing regulatory requirements in the Russian federation make the submission process complicated.
ICH guidelines have been adapted as regional regulations both in the US and the EU but there are significant differences in the manner these guidelines are interpreted in each region. While the eCTD/CTD format has been established in ICH M4, it was also incorporated in the US as Guidance for Industry and Notice to Applicants in Europe.
In the US, the eCTD format is mandatory for NDAs, BLAs and ANDAs since May 5th 2017 and all commercial INDs and master files have to be submitted in the eCTD format since May 5 2018. In the EU, eCTD has been mandatory for all centralised procedures since 2010, for all DCP/MRP Procedures from January 2018 and for all new National applications, it is mandatory to follow the eCTD format since July 1st 2018.
One of the key challenges with the US FDA is the manner in which the data is handled, with eSubmissions, requiring the copies of the clinical research files (CRFS) and datasets from the outset along with the submission of Nonclinical datasets. There may as well be other requirements such as the submission of adjudication packages and the Medwatch forms. Another key requirement for the US FDA eSubmissions includes the submission of the Nonclinical and Clinical reports with the Study Tagging File (STF), which is a mini XML backbone that can be used to manage the contents of each report. As the eCTD format is also used in the IND phase, the use of lifecycle management capability of eCTD in the IND can reduce the workload later. The FDA also allows for direct cross referencing from the NDA eCTD back to content first submitted as part of the IND.
As for the content of the eCTD, for example, Modules 2 and 3 referring to the quality of the drug product in the CTD/eCTD, USFDA assessors look for the data to evaluate the drug product while the assessors in the EU rely on the critical aspects of the product. In general, the FDA asks for as much data as feasible to come to a critical evaluation while in the EU, the application submission is more descriptive in content and selected data is provided which is extracted from GMP sources. The Module 3 in the US CTD explicitly requires GMP and documents related to batch records and the EU specifically excludes GMP documents.
Regulatory guidelines in each region may also result in different recommendations with respect to the study design and defining the clinical endpoints. The selection of comparators may also be different in the EU and the US. Furthermore, the consultation between the sponsor and the regulatory authority in the US and the EU via pre-submission meetings and scientific advice respectively may result in different feedback. The requirement for statistical methods may be different in the US and the EU and so is the handling of missing data in the clinical trials. All these aspects impact the content preparation for clinical Module 5 of the CTD. When clinical studies are conducted outside the EU, an extra assessment needs to be performed if the study findings are representative for the majority of EU population, especially concerning the difference between the racial make-up between regions [5]. For the EU, if the study population is outside Europe, an assessment of products efficacy in the European population should be conducted by the sponsor of the marketing authorisation application (MAA). The USFDA requires a submission of summaries of the integrated efficacy and safety analysis in the Clinical Study Reports (CSRs) [6] whereas the MAA in the EU does not require a submission of these summaries in the CSRs but in Modules 2.7.3 and 2.7.4 respectively in the CTD. Importantly, the two regions may have completely different legal basis for the application and therefore the application content from one region may require substantial modifications before the content can be submitted to the other region.
Implementation of eCTD across world regions has been scheduled across different world regions and will be accomplished in future as there have been regions and countries that have only started to implement the electronic submission of applications to the regulatory agencies.
The requirements of specific countries and regions for a paper format of applications, stability and clinical datasets and country-specific GMP certification procedures present major challenges in the uniform acceptance of the eCTD. However, the option to extract data for each region from the core eCTD, along with the reusability of content, makes eCTD an attractive tool. It allows pharmaceutical companies to increase efficiency in the submission procedures while also helping with maintenance of marketing authorisations when planning an application for global submission.
1. Heß, C.H., Expectations of eCTD 4.0 – also a step forward for small and medium sized enterprises? 2018, University of Bonn. 2. Silva, L.d., Critical Assessment -Implementation of ICH Guidelines in Brazil. 2018, University of Bonn. 3. Huynh-Ba, K. and A. Beumer Sassi, ANVISA: an introduction to a new regulatory agency with many challenges. AAPS Open, 2018. 4(1): p. 9. 4. Soltitskaya, A., Some Specific Regulatory Aspects and Nuances of Drug Products Localization in the Russian Federation. Journal of Pharmacovigilance, 2018. 06. 5. CHMP, Reflection Paper on the Extrapolation of Results from Clinical Studies Conducted Outside the EU to the EU Population. 2009: London. 6. USFDA, Integrated Summary of Effectiveness Guidance for Industry FDA, Editor. 2015.
Poonam Balani has a PhD in biomedical sciences with 14 years of experience in medical and academic writing.