A lot rides on an NDA. All the hard work that has preceded it, along with significant investments of resources and time, makes the submission a watershed moment in every new drug’s journey.
Indeed, failure to pass the FDA’s requirements can spell the end for a new drug or at the very least the beginning of a long route back to resubmission.
Consequences Of An Incomplete NDA Submission
This is why Dr. Nicola Davies warns in the Pharma Letter that every NDA submission should be complete. This sounds simple, but the FDA will refuse any application that does not meet its stringent requirements.
Davies warns that the FDA’s refusal could arise when applications are “materially deficient or disorganized” or when there is “information lacking on any one of the disease indications.”
Applicants must have completed more than one clinical trial before the NDA submission and have full assessments on hand of any “potential abuse of the drug.”
The ramifications of a refuted application can be detrimental to finances and reputation, Davies cautions, citing a Florida-based biopharmaceutical company suffering a 37-percent “price drop within a day of receiving a RTF letter.” Another pharmaceutical company dropped 80 percent in stock value and had to retrench 20 percent of its workforce after failing to pass its application.
Where Applicants Go Wrong
This is the risk of refusal in more numbers. Derek Lowe at Science Translational Magazine, says that of unsuccessful first-time applications:
- 15.9 percent were due to “uncertainties related to dose selection.”
- 13.2 percent failed to have their endpoints reflect a “clinically meaningful effect.”
- 13.2 percent showed “inconsistent results when different endpoints were tested.”
- 11.3 percent showed “inconsistent results when different trials or study sites were compared.”
- 13.2 percent revealed low efficacy “compared with the standard of care.”
But as Lowe reminds readers, this stringent regulatory process is positive because it keeps drugs at a higher quality and patient safety paramount. He rebuffs those who call for greater freedom from the medical community and marketplace.
Make Time Your Ally
Applicants submitting an NDA need to have time on their side. Tim Garver, Ph.D., EVP and chief operating officer at Impact Pharma, advises organizations to begin planning the submission 12 to 18 months before the deadline.
This means completing pivotal trials, nonclinical requirements and final special population studies will definitely be possible. There is also “manufacturing scale-up and final stability data” to consider. This is all before the pre‑NDA meeting, compiling a list of “possible FDA Advisory Committee Meeting vendors and external support” and completing the NDA documents.
It’s for these reasons that Garver suggests creating a key messages document to hold “every important message” relevant for the application in one place. It also acts as to “identify the main data/results that support the message as well as the location, within the application, where you need to be presenting these data/results in support of the message.”
Seek Advice From An Independent Third Party
Dr. Lars-Helge Stromquist [registration required], who founded the NDA Group in 1997, says succeeding at an NDA is about “doing the right things right first time.”
This often means seeking advice from qualified scientific third-parties for “input and second opinion on the drug development programme.” This helps to rid the process of internal biases.
The European Medical Agency (EMA) reports that “obtaining and complying with scientific advice appears to be a predictor of outcome” for a successful NDA. He cites the FDA, EMA, the European National Competent Authorities and the NDA Advisory Board as valuable third-party sources.
Stromquist suggests getting advice at the following stages:
- Non-clinical plan
- Phase I plan
- Phase II plan
- Phase III plan
Understand the Difference Between Data You Have and Need
at Rho World say a major flaw they see in sponsors’ NDA submissions is a lack of understanding of the data they have and how that charts the way to approval.
The trio argues that successful submissions rely on “in depth understanding of how the data you have from your clinical studies, nonclinical studies, and Chemistry, Manufacturing and Controls (CMC) / Quality development map to the requirements of the application.”
While these requirements might be specific to a regulatory authority or area of therapy, the trio warn that these are always changing as science advances.
Perform a Gap Analysis
This is why, they argue, a gap analysis is vital. “Performing the gap analysis at this stage of development will also provide enough time to conduct additional nonclinical studies or CMC development that may be needed to support the application,” they write.
For smaller and medium-sized companies, a CRO might be required to complete the gap analysis, but doing so will provide “a detailed look at the existing data and regulatory communications.”
This includes data format such as CDISC — that goes for data from legacy studies, too — as well as claims made on the label.
Collection and proper analysis of data will highlight what is missing in the database or reveal what is unnecessary to support the application, especially legacy data that can be costly converting it to CDISC format.
Rapti D. Madurawe, Ph.D., branch chief at the office of New Drug Quality Assessment at the FDA, says it’s essential that the data shows the drug to be marketed has the same “identity, quality, purity and strength as that of the investigational drug proven to be effective and safe through clinical studies.” Applicants wanting to succeed with their NDA submission should be able to “demonstrate consistency and reliability” of the drug manufacturing process over product life, Madurawe states.
Partner With The Right CRO
Rob Woolson at Rho, Inc. says applicants should seek the right CROs if getting help for NDA submissions.
Most cover two categories:
- Technical data standards services, which involve the conversion of clinical datasets to CDISC formats and “generating datasets for the integrated summary of safety (ISS) and integrated summary of efficacy (ISE).”
- Regulatory and medical writing services.
Use Biostatistics Effectively
However, much needs to be done between these two offerings, Woolson says, such as biostatistics submission services.
These services fall into two sub-categories: marketing application services and regulatory interaction support.
The former concerns “analysis plan development; data standards plan development; supporting regulatory and medical writing during the submission process; pooled data assessment; and analyses to support key messages.”
Regulatory interaction is about inputting and analyzing biostatistics for meetings and communications with FDA. Having biostatistics and data standards expertise on-hand will assist with FDA communications, especially as to when you should “initiate conversations with FDA over your data.”