How To Tell A Compelling CMC Story In Your NDA/BLA Application

Storytelling is integral to the pharmaceutical regulatory process. It’s really what your new drug application (NDA) or biologics license application (BLA) is all about. It’s about deciphering the data to tell a reviewer how your process and product works.

There is an art to building the story, writing the submission and presenting the data. How much should be included? Is the data clear or is it difficult to decipher? One of the issues with the application process is there is often a tendency to have one person write the entire submission, which can result in the CMC section being an afterthought.

“A common perception is you fill out Module 3, put the summary together, and that's it, because the real glamour is the clinical data,” says Brian Lihou, General Manager at DSI, a ProductLife Group company. “But the CMC section of a common technical document (CTD) is supposed to demonstrate a state of control over the product and having the supportive documentation for that is often overlooked.”

The challenge for companies is that while the format for the submission process is fairly well laid out – with summaries, reports, and data — there's considerable latitude for assimilating, discussing, comparing, and contrasting the information and determining how much information to include.

Ed Narke, Co-Founder and Sr. Regulatory Strategist at DSI, says the focus needs to be on building the Module 3 to demonstrate the quality of the drug product. To get that right, it’s advisable to start early in the review process.

“When you begin an IND submission, start to put stuff together, build a strategy document, lay out a plan, work with your vendors, maybe bring a consultant in to outline that, speak with the FDA, put questions out there that you know are going to come up at some point and that you're going to not know the answer for,” Narke said.

Another key element to crafting a strong submission is including a balance of technical expertise and regulatory experience by having a technical team member involved in content development and regulatory oversight to guide the story through submission.

Building Resources and Partnerships

The regulatory requirements for a submission are the same for any company, regardless of size. A combined challenge exists for pharmaceutical companies: resource constraints and inexperience with the submission process. One way to manage this challenge is to have a CMC regulatory consultancy manage aspects of the submission while handling some sections internally, creating an opportunity to grow the skills in-house.

“When we work with a client in this way, there are several key components that we require: There must be project management – whether with the client or from our side — and there has to be true traceability of each of the sections as they progress through the different stages of authoring,” Lihou said.

It’s also important to have a team member manage the technical review to make sure the source information correlates with what is written in the submission, as well as a regulatory review. The regulatory lead is responsible for ensuring all the authors of the various components follow a cohesive story. Another important member of the team is a formatter who has prior experiences with the templates and the intricacies of formatting tables and can quickly make each section review-ready.

“Our team typically comprises an author, a regulatory lead, a subject matter expert for the particular discipline – analytical, drug substance, drug product, etc. – and a formatting person, all overseen by a project manager,” Lihou noted. “The regulatory lead has ultimate say over the content and direction of the filing and must therefore be in lockstep with the expectations and strategy of the client.”

Since each company and every submission is different, it’s important that someone at the sponsor company understands and is transparent about all the gaps and issues and understands their document library.

The key to successfully managing the submission process is having an appreciation for the expertise, role, and commitment of each team member who brought the project to the stage of product application. Trust between the team members involved in development and the submission author will help ensure a more seamless exchange of information.

Sponsor Readiness – Getting Comfortable With Templates

The word template is sometimes not in a sponsor company’s lexicon. Deciding which templates to use is a key step when preparing a marketing application. The thought process should begin in CTD with a chart of all the eCTD sections outlined. Once a team knows what will go into those sections, they should start thinking about templates.

“A lot of sponsors are confused about what goes where and why it's important but having that clear ahead of time will help them to more clearly map out the submission story,” said Meranda Parascandola, Head of Business Development and Marketing at DSI.

Later problems can be avoided by making use of templates to place the right information in the correct sections and later fill in compliance information and additional data.

“When you get to the last stage, and you have good clinical data, but your story is incomplete, that’s where reviewers will find issues,” Narke said.

While there is a time and financial investment to authoring submissions, the cost of an incomplete filing is monumental. That doesn’t mean it has to be a solo endeavor. Regulatory authorities are willing to provide advice, allowing companies set up meetings with the regulators to ask specific questions.

“Ask questions that you can get something out of, maybe based on deciding when to do things or something that you might want to document and have an agreement that's binding that you can come back to,” Narke said. “If it’s a fast-track program, have post-marketing commitments. Equally, make sure the reviewer clearly understands the science behind your process. Authorities don’t expect a company to agree with everything they tell them to do in every instance. Still, they do expect thoughtful considerations and scientifically justified responses and strategies.” Every program is different, but there are steps that every company can take to mitigate problems in the application process. Make sure you identify any CMC issues throughout the program and any changes during the process, so you have adequate time – and data – to respond to regulatory concerns.