The eCTD struggle is real.
Regulatory submissions must conform to the electronic common technical document (eCTD) format to be successfully received and reviewed by health authorities. And while this might seem simple, this complex technical process is actually rife with risk if you lack expertise in medical writing and regulatory publishing.
In this blog post, I’ll discuss common pitfalls sponsors encounter in the drug submission process and some best practices for addressing them.
A brief history of the eCTD
The concept of the eCTD was developed by the International Conference for Harmonization (ICH) Multidisciplinary Group 2 Expert Working Group. This working group is an international organization that develops international standards (ISOs).
Their idea was that the CTD (eventually eCTD) could be implemented by every health authority globally to streamline regulatory review of new drugs, and potentially all regulated products. The eCTD contains 5 modules:
- Administrative information and prescribing information
- Common technical document summaries
- Quality
- Nonclinical study reports
- Clinical study reports
Modules 2-5 are the common modules of the eCTD. The idea was that once a Sponsor developed the content for modules two through five, they could reuse it for submissions wherever eCTD is accepted: the US, Canada, the European Union, etc.
A cautionary tale
Recently, I met with a prospect to discuss how we could help them prepare a submission. This organization’s drug candidate is in phase three trials and has received significant venture capital investment. The staff consisted of experienced scientists from academia. So, their experience was really in disease research, and they didn’t spend a lot of time focusing on eCTD.
For them, getting documents into an eCTD format using templates was a challenge. Their staff was writing reports without following the eCTD format. And they also weren’t collecting the data from studies to conform to eCTD requirements.
By not having their submission conform to eCTD standards, this sponsor could risk a delay in submission which would lead to a delay in approval. This obviously puts pressure on financing the business, treating patients, and maximizing patent length. Also, receiving a “refusal to file” (RTF) from the FDA adds to the time and cost of developing a drug by delaying its review. The submission has failed, sometimes within just minutes of arriving at the agency.
RTFs: How they happen and how to mitigate your risk
Here are two common regulatory pitfalls that can invoke an RTF.
- The submission fails based on technical When the FDA receives a submission, they run it through a Global Submit Validate tool. If the submission has serious validation errors (High Errors), they will reject it immediately. For example, the folder structures, files, or XMLs don’t meet the validation criteria.
- The submission fails based on content For example, you didn’t include case report forms. Or the data is not in CDISC format. Or you forgot to include an integrated safety summary report, which summarizes all the safety information in the submission.
During the transition period from paper submissions to eCTD, the agency issued many RTFs as sponsors learned how to implement processes for complying with this regulation. And it still happens today.
Ensuring high quality submissions
By embracing regulatory operations best practices, sponsors can avoid the risks of failing to meet eCTD standards and thus incurring an RTF from the agency.
First, we can help from a regulatory writing standpoint by supporting project management and medical writing of the necessary studies. Once the medical writing is complete and the documents are prepared for the eCTD submission, our publishing services team can manage the project from a submissions standpoint. This means that they add the needed reports to the eCTD publishing software and ensure that the submission is valid and will be accepted by the agency the first time.
Satisfying regional requirements
You may be thinking to yourself, “OK, eCTD modules 2-5 are common. I just have to get them right, and I’m set!”
Not so fast.
eCTD requirements differ between regions in two major ways: differences in module 1 content and validation criteria.
eCTD module 1 contains regional requirements: the prescribing information, packaging, local government forms (eg, PDUFA user fees in the U.S). Each region has its own submission specifications and requirements. For example, the European Union can accept submissions using their “centralized procedure,” which grants approval to market a drug in all EU countries.
Additionally, each region has their own validation criteria by which they scrutinize submissions for errors. So, every time a country or region updates their validation criteria or local requirements, we update the version of our submission validation software for that specific country or region.
I hope that you now appreciate the complexities involved in developing an eCTD submission. To learn more about how to implement eCTD via outsourcing, please read a white paper that we’ve written on this topic.
