The new drug application or biologics license application (NDA/BLA) process must be started early and documented comprehensively. Businesses producing novel products should apply to perform clinical trials by submitting an investigational new drug (IND) long before marketing approval has been gained.
The IND is a blueprint for the rest of the program, which makes it essential to collect the necessary data.
Image Credit: DSI, a PLG Company
This will include data on the effectiveness of the active ingredient, batch specifications to validate uniformity, excipients, storage units, and, in the example of new excipients, data about the procedure to create that excipient.
Co-founder and chief regulatory scientist at DSI, a ProductLife Group company, Ed Narke calls this the recipe for the consistent production of the drug product.
If you keep a record of all this information, what you’re expecting in each area, when you expect to get data and how much, it can go toward your regulatory strategy document, which, eventually, along with updates, becomes your NDA.”
Ed Narke, Co-Founder and Chief Regulatory Scientist, DSI, a ProductLife Group Company.
Regulatory consultancies, when they are asked to help with their NDA, are often asked by clients why it takes a much longer time to write an NDA compared to an IND.
The amount of time required usually depends on the type of business.
Large, vertically-integrated pharmaceutical organizations with many resources are able to build an IND that is highly defined with the appropriate amount of data while keeping R&D information that can be employed later or may never be used due to predicted changes.
A very simple IND may be filed by emerging, small biotech businesses, the majority of which begin in academia. When the business reaches Phase 2 or Phase 3 and begins to observe positive efficacy data, there may be a sudden need to file an NDA.
“However, you’re starting from an IND that includes maybe 5 percent of what’s needed in the NDA,” Ed explains.
“You don’t have the conformance information, how you got to this process, how the process has been scaled and controlled, how changes in the process affect the control of the product, how the methods were selected, if they were qualified and why, and how were they validated. Because the idea has not been properly developed in the lead up, you’re going to have to do a lot of work putting an NDA together.”
What is the story?
Another factor in the preparation of an NDA is creating a storyboard that combines communication from the various functions to create cohesion and ensure clarity in everything that goes into the submission, including analytical, regulatory, business development, marketing and quality assurance.
The business can then develop this storyboard into the NDA or IND, using the source data to build it. “That’s the art of writing a submission,” Ed states.
Beyond this, the perspective of the health authority must be considered. The only way to truly build an understanding of whether the story will make sense to the authority is through expertise.
“You have to help the reviewer address two questions: where does the sponsor want the reviewer to go, versus where does the science tell the reviewer to go,” Ed explains. “What both parties need to consider is ‘what does common sense tell me?’”
Authoring and quality control
Even if the IND is fairly detailed, the quality checking and authoring of the NDA document will be challenging, where a multi-disciplined team of experts are brought in to produce documents of a high quality.
The procedure starts by collecting the source data, for example, the batch records, GMP documentation, specifications, methods, development reports and more.
“Take an inventory of what you have before you start authoring, because some information may interrupt how you write things or the order in which you prepare your content,” Ed states.
“You’ll want to do a content review. You’ll want to get group consensus on how that material and information will be put together and cross-referenced. You’ll want to do some data accuracy checks, especially for questionable source information. And, ultimately, you’re going to want to format it.”
DSI general manager Brian Lihou adds that it is crucial to adhere to the structure established on the common technical document (CTD) format.
“We will start with a pre-determined checklist of documents broken down by section,” Brian states of DSI’s procedure.
“The client will put them in a file transfer site based on where they need to go, so you have all of your sources of information broken down by the sections. You ask for all agency correspondences, anything that paints the flavor of the document that you’re going to write, any past or future commitments. Then you have the regulatory expectations, which a regulatory author will draft.”
“Then we’ll have our technical person QC those sections against the relevant source information. Next, there are comments and a regulatory strategy check to make sure you’re telling a cohesive story. Version control is essential. You make sure that you control what gets sent and what comes back.”
To make the submission process more efficient, there is always a drive to get the NDA finished quickly. It is important to begin early with the writing, at the start of the IND, and to maintain this process for the duration.
It is important to keep track of the data that is pending, work out discrepancies in interpretations before the work is finalized, and ensure transparency for each section as it is written.
A balance must be achieved between quality and timekeeping. Having balances and checks in the authoring workflow is essential to successfully remediate comments and questions.
“Having that transparency per section throughout the CTD helps everyone overall. Sometimes it is a bit cumbersome and labor-intensive, but it pays off in the long run, especially when you’re working in a relatively condensed timeline,” Brian notes.
Here, there and everywhere
Businesses must now consider developing and authoring their BLAs or NDAs for various markets.
While the United States may be where the initial NDA is completed, there is a population of patients in Europe and additional markets for the products, so it makes sense to file in other locations or license out the rights to these markets.
While the CTD created by the International Council for Harmonization (ICH) is used as a shared global drug development structure, there are differences according to region.
“There are certainly stability requirement differences and even specification differences,” Ed says. “Then if you get into biologics, there are quite a number of significant differences.”
Businesses exploring rest-of-the-world NDAs must evaluate the unique guidelines when producing their regulatory strategy document along with the consequences for the organization in general and whether value is being created.
Be prepared
Wherever and whenever an NDA is submitted, responses must be prepared for the anticipated questions so that time is not lost. There will always be questions, so ensure a strategy is in place.
Acknowledgments
Produced from materials originally authored by Meranda Parascandola from Design Space InPharmatics.
About DS InPharmatics 
DS InPharmatics (DSI) provides regulatory, technical, and project management consulting services to healthcare product companies that manufacture and/or market pharmaceuticals, biopharmaceuticals, and cellular and gene therapy products.
Since 2007 we have provided our clients with innovative strategies and exceptional quality work products intended to enhance product development, approval, and marketing presence. Whether advocating CMC strategy, directing CMC operations or developing CMC submission content that represent the best interests of emerging biotech, we focus on the critical CMC issues and build programs that enhance development.
In April 2021 we were thrilled to announce that DSI has just become part of ProductLife Group.
French-headquartered ProductLife Group (PLG) is well-known in the Life Sciences market. It has a track record of successfully managing global outsourcing programs and insourcing services for its international client base. The company is on a mission to help transform human health outcomes by optimizing regulatory affairs, safety & vigilance, and quality compliance for life sciences organizations worldwide.
The fit between our two organizations could not be more perfect. We will complement PLG's growing biotech services portfolio. US biotech sponsors recognize DSI as a leader in consulting for go-to-market strategies and RA pre-market consulting. At the same time, PLG has a strong reputation for managing end-to-end outsourcing of regulatory affairs and pharmacovigilance activities worldwide.
Our merger with PLG will harness our combined strengths, offering our clients on both sides of the Atlantic support with their developed drugs approvals and post-approvals compliance, plus advisory services on the best market strategies to deliver a rapid ROI on their development. Together we will offer our clients increased pharmacovigilance capabilities - including a QPPV; pharmacovigilance consulting; and a fully validated safety database - as well as complementary toxicology-related services; RIM/electronic document management services; and support for medical device regulatory requirements.
We see enormous potential in this new chapter for DSI and you, our clients. As a PLG company, we have the opportunity to become part of a global force in life sciences regulatory and compliance solutions and services, and we're incredibly excited to add our momentum to that effort.
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