Articles

Newsletter Winter 2019 From Kinexum Founder: Staying on the NDA Learning Curve

By Alexander Fleming

Executive Chairman

This email address is being protected from spambots. You need JavaScript enabled to view it.

I was once—literally—the poster child for New Drug Application (NDA) review at FDA.

I arrived at FDA in 1986, thinking my time there would be a sabbatical from NIH. Shortly after my arrival, the editor of the FDA Consumer Magazine asked if I would appear in an article about NDA review at the Agency. I agreed. Magazine staff then set me down in the document room of my division on the 14th floor of the Parklawn Building. They took my picture: a young tike perusing a 4-inch volume from an NDA, with 500 volumes in the background. I don’t recall if these volumes were actually an NDA that I reviewed, but they could have been the lovastatin NDA. By sheer luck, I was handed lovastatin as my first NDA review a few weeks after joining the Agency. Also lucky for me, this first-in-class statin generated much excitement and attention in the press. Statins went on to become one the most important drug classes for chronic diseases ever and led to Nobel prizes for Brown and Goldstein.

 

Being very green, I did not know any better than to put my shoulder to the lovastatin review. I also encouraged my colleagues to hurry up on their reviews, some of whom were rather perturbed by my pushiness. The result was a quantum leap in the speed of NDA review. Lovastatin was approved in 11 months—the average time to NDA approval at the time was over 2.5 years. CDER Director Carl Peck in an all-hands meeting raised lovastatin as the model for NDA review. All of this led to many other unmerited opportunities and adventures at FDA.

 

At the time of my first NDA review, I thought I was on the steepest learning curve that I would ever face. The torrent of all the principles and practices of therapeutic evaluation made my training and early research in metabolism and endocrinology seem trivial.

 

Learning curves for us all have only gotten steeper, which is both good and bad. They’re good for making life exuberantly exciting, but they’re bad for keeping us awake at night recounting how many desperately important articles and books had been left unopened on the table. 

 

Susan Manley’s article on NDA planning, featured in this issue of Kinexions, reminds me how I have fallen off the learning curve for compiling NDAs. Although I am frequently involved in NDA design, preparation, and prosecution, I have fallen off the curve in understanding today’s process of building an NDA, which has dramatically changed over the past three decades. One difference is the sheer volume of data and narratives involved. The 500 volumes of the lovastatin NDA could be put on a $4 memory stick, but a multi-terabyte hard drive is required to accommodate today’s typical NDA. Another difference is the standards for clinical and nonclinical reviews. Although the current digitalized submission and reviewing system facilitate NDA review at FDA, the expectations for data handling, document management, analysis, and interpretation have exponentially increased. My 80-page lovastatin review would not make the cut by today’s standards.

 

Although old-timers like myself have fallen off some learning curves, this doesn’t mean we have to give up. Instead, we should strive to remain on the learning curves of the areas on which we continue to focus.

 

Susan and I started our professional careers at about the same time, though we were in different roles: I in clinical evaluation, she in regulatory and project managementan equally challenging ballpark. Susan exemplifies someone who has maintained her craft in the guild of NDA builders. She has stayed on the still steep learning curve for NDA design and construction, an enterprise comparable to building a cathedral. My hat is off to her and other craftsmen who have stayed on that learning curve.