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International Clinical Trials

Submission Statement

 

Finding ways to navigate the Clinical Trial Directive regulatory labyrinth remains high on every pharmaceutical company’s list; documentation streamlining and use of the eCTD format offer much needed clarity and direction. The focus on clinical trials and clinical trial applications (CTAs) has been sharpened in recent years. A number of initiatives have been implemented to harmonise the conduct of clinical trials in Europe, the most notable of which is the 2004 Clinical Trial Directive (2001/20/EC) (1). This Directive implemented a broader EU view on clinical trials, including a common format for CTAs, and was followed by the Voluntary Harmonisation Procedure (VHP), adopted throughout the EU for assessment of multinational CTAs (2).

Although harmonisation is in progress, the approval of CTAs is still regulated nationally and often requires additional national documentation. In addition, the submission format varies among the different EU countries. Development costs are increasing for all pharmaceutical companies and this is especially significant for smaller investor-supported companies and SMEs, where workflows need to be as lean as possible. The electronic common technical document (eCTD) submission format can be a rational, cost-effective and long-term solution designed to maximise the efficiency of regulatory processes (3).

The eCTD submission format is already used in the US process for electronic investigational new drug submissions (eINDs), allowing concurrent compilation of the new drug application (NDA) during the development of a new drug product (4,5). In terms of making progress at the global stage, a common submission format in Europe and the US would provide real benefit.

The US eIND Model

In the US the IND may be prepared as an eCTD according to the ICH M2 EWG – the Electronic Common Technical Document Specification (3). IND Module 1 follows the same structure as the NDA according to the document ‘FDA – Comprehensive Table of Contents Headings and Hierarchy’ (6). For example, the Investigators’ Brochure is located in the labelling section, the IND Annual Reports are located in the US Module 1 section 1.13 Annual Report, while the clinical trial protocol is found in Module 5.

This means that, in the US, the compilation of the Phase 1 IND is prepared as an eCTD, and includes the necessary documents to support the Phase 1 trial(s). Phase 2 and 3 protocols, along with additional supporting documentation, are added successively to the eCTD structure. Thus the marketing authorisation application (the NDA) is compiled concurrently with the development process, rather than being a separate document to be prepared de novo at the end of a lengthy development programme.

Electronic CTA Submission Possibilities in the EU

Given that the eCTD format is not accepted for CTAs in the EU, the current status of CTA submission in other electronic formats has been investigated, using the national competent authorities (NCAs) homepages as the source (7). A search was performed in October 2011 and February 2012, the results of the which are shown in Table 1, indicating that the electronic filing of CTAs is still not common. Furthermore, the format of and process for electronic submissions varies between countries. Pharmaceutical companies find the process of preparing multiple, slightly different submissions a burden; to maximise efficiency and reduce development costs, these organisations prefer to have one common process for submission in Europe.

Despite the different requirements for the various CTA submission format, all countries require the EudraCT application form as XML-file on a CD-ROM. The full benefit of this submission could be employed by using the eCTD XML backbone for the entire CTA documentation.

Current State of eCTD Submissions in the EU

Since 2010 when the NCAs implemented the eCTDs, the recommended format for marketing authorisation approvals (MAAs) progressed rapidly within Europe, and the use of paper is now very rare. In the Czech Republic, for example, the eCTD format is now mandatory. Pharmaceutical companies are thus getting used to working in the eCTD environment and wish to adopt these work processes at all stages in the development of new drugs.

An eCTA model for Europe would be a major step forward for development companies, especially SMEs, as the documentation can be prepared as common module 2-5 for clinical trials performed in the EU and US. This would save time and ensure simultaneous submission of substantial amendments. Moreover, this will enable SMEs to keep the regulatory resource burden low.

 

Preparation of e-Compatible Documentation for CTAs: Beneficial but not Required

Planning a regulatory strategy and the processes needed for electronic compilation and submissions, including the writing of documentation in e-compatible templates, results in a streamlined development process that is focused on preparing the required documents right from the beginning – that is, application documents are prepared in the appropriate granularity and in e-compatible formats from their first versions.

As mentioned, it would be preferable for submission formats and processes to be as harmonised as possible and have a single submission through a common gateway in the EU. The easiest approach would be to implement the eCTD format already familiar to both companies and the NCAs for CTAs; this would enable the NCAs to be able to use already implemented review tools. The EudraCT database may be a solution for a common submission gateway.

CTA-CTD Mapping

Although the eCTD format is not currently required for CTAs, companies can already benefit from using e-compatible templates when preparing clinical trial documentation and in this way create common documentation for the CTA and the eIND. Further, the documentation would already be prepared in the right format for the future MAA submitted as eCTDs.

The eIND may be prepared as the core clinical documentation from which companies use appropriate modules for the EU IMPD, Scientifi c Advice briefing packages and paediatric investigation plan (PIP) applications.

Table 2 shows a possible CT CTD mapping model based on the electronic structure of the VHP application (see Figure 1) and the CTD triangle (see Figure 2). This mapping illustrates how the VHP table of contents can be transferred into CTD documentation granularity.

Joint global development between the US and the EU is a common approach for pharmaceutical companies, thus part submissions and consolidated sequences of the eIND for EU CTAs and other EU submissions would ensure identical documentation globally. This would enable efficient version control, improve traceability, and facilitate life cycle submission and documentation management. The document may be produced on electronic media or paper as required in the appropriate EU country.

The rational approach adopted for eCTDs would in this way also be used for EU CTAs and other submissions required during development of a new drug product. Partner audits and transfer of documentation would also be greatly facilitated by use of the eCTD format.

 

Conclusion

Both industry and regulatory authorities can already benefit from preparing e-compatible clinical trial documentation, using a well-known documentation format and content. The stakeholders in the CTA process will gain time and resources from implementing an eCTA process, which can be of benefit to the patients, who might get quicker access to new innovative treatments.

With the focus being placed on the eCTD submission life cycle as well as the document life cycle, the time spent on future regulatory submissions can be reduced by preparing e-compatible common documentation from the early stage of the development as well as by preparing the Phase 1 CTA as eCTD the build of the future MAA is started.

As a result, the preparation of the common module 2-5 documentation for EU and US clinical trial applications using the eCTD as CTA submission format, the receipt, processing, and review of CTAs are improved. In addition the use of the eCTD backbone files facilitates the efficient submission handling and streamlines the different submission types during development.

References

  1. Clinical Trial Directive (2001/20/EC)
  2. Guidance document for a Voluntary Harmonisation Procedure (VHP) for the assessment of multinational Clinical Trial Applications, CTFG//VHP/2010/Rev, March 2010
  3. ICH M2 EWG – Electronic Common Technical Document Specification
  4. 21CFR Part 312 Investigational New Drug Application (IND)
  5. Guidance for Industry – Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical Product Applications and Related Submission Using the eCTD Specifications
  6. FDA – Comprehensive Table of Contents Headings and Hierarchy
  7. Internal study report on use of electronic submission in EU, 2012
  8. EU Module 1 Specification
  9. Organisation of the Common Technical Document for the Registration of Pharmaceuticals for Human Use M4
  10. Cance P and Goode K, A Better Deal in Europe, International Clinical Trials 11: pp96-98, 2011
  11. 11. Lorenz RA, The challenges of ePublishing in regulatory affairs – obstacles to overcome on the way to: “Veni Vidi Publicati”, International Pharmaceutical Industry 3(2): pp14-16, 2011

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Helle Ørbæk is Head of QA and Document Management at IWA Consulting, a regulatory affairs consulting company. Helle has 11 years’ regulatory experience working with development projects, EDMS and CTD. Helle is specialised in eCTD strategies, preparation and submission in EU and US and life cycle management. Helle has six years’ experience within QA and has successfully implemented the quality management system at IWAC (ISO 9001 certified 2009). Before embarking on her regulatory career, she has worked within healthcare since 1980. Helle holds an IPMA Certifi cation in Project Management, Diploma in Business Organisation and Medical Secretary Education.

For more than 20 years, Lillan Rejkjær has worked in pharmaceutical development, with responsibilities including project development management and leadership from initial idea to clinical product, development of overall regulatory, nonclinical and clinical development strategies for project compounds according to ICH guidelines, life cycle management and pharmacovigilance. Lillan received her degree in DDS from the Royal Dental School (Copenhagen University) in 1983 and a Master of Public Health from Copenhagen University in 2008.

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Helle Ørbæk
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Lillan Rejkjær
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