Pfizer's Gene Therapy CMC Woes: A (Not So) Cinderella Story

By Anna Rose Welch, Editorial & Community Director, Advancing RNA

As a poet and violinist and the daughter of an artist, it makes perfect sense that I’d end up in the technical CGT manufacturing space — said no one in the history of ever. I blame my background and genetics for my endless desire to take creative liberties with the scientific knowledge I glean day in and day out. And, dear reader, for better or worse, my brain has been getting kicked into creative overdrive more and more regularly these days. (You’re welcome?)

Earlier this month, for example, I felt some creative stirrings after reading — of all things — the transcript for Pfizer’s latest earnings call, which included updates on its ongoing gene therapy programs. What was I thinking about as I read some of the surprising news contained in that earnings report, you may ask? None other than the “Work Song” in Cinderella.

Regardless of how insane that might sound, there is actually a critical industry challenge taking shape in Pfizer’s updates that you CGT CMC peeps really should be watching moving forward. It just so happens that what the CGT industry needs — regulatory scientific alignment/convergence — is best depicted by a team of singing woodland creatures stitching together a ballgown.

In recent weeks, the headlines have been calling attention to the delays Pfizer encountered in its hemophilia gene therapy clinical trials. But the news I found just as, if not more, notable was contained in this quote by Mikael Dolsten, president, worldwide research and development and medical for Pfizer, who gave an update on the company’s (also delayed) DMD gene therapy program:

A few sites [testing the DMD gene therapy] have resumed new patient activities, and we anticipate that nearly all ex-U.S. trial sites will have restarted clinical activity [following a recent protocol change] by the end of this month…. In addition, we continue to work with the FDA to address outstanding IND questions related to the Phase 3 study, including technical aspects of our potency assay matrix. We have made considerable progress with development of the CMC assay as per FDA guidance and are now in an active phase of filing this update. While we cannot speculate as to when sites may open, we're working to reach alignment with the FDA as soon as possible. *I added the bolding/underlining for more emphasis and brackets for clarity.

We really haven’t gotten to the point in the overall maturity of the regulatory pathway at which convergence/scientific alignment takes center stage. We’re mostly concerned with getting clear-cut guidance and figuring out what the P’s and Q’s of a reasonable and efficient — but still scientifically thorough — CMC dossier should be from regulator to regulator.  

However, as Pfizer’s situation demonstrates, for companies pursuing global development programs, misalignment around the CMC package — particularly that beastly potency assay — can have grave consequences for patients and development timelines. I was surprised by how little fuss there was over Pfizer’s announcement in May that, while the EMA signed off on its potency assay, the FDA was less amenable to one of the “supportive” assays in the potency matrix. This disagreement, by the way, kept the U.S. Phase 3 trial sites from opening at all — a mind-boggling fact, seeing as several different regulators thought this assay was sound enough to proceed with Phase 3 trials in eight countries (including Europe, Canada, Japan, and the U.K.).

Regulatory scientific alignment/convergence is and will always be a work in progress because regulators (believe it or not) are humans with different appetites for risk. It’s highly unlikely regulators the world over will agree on every fundamental scientific concept, have the same appetite for risk, and, in turn, require all the same data gleaned using all the same methods. (As I wrote in a blog post earlier this year, “Regulatory Harmonization,” despite how sexy it sounds, is also a whole other bucket of worms that is even less likely to be accomplished than scientific alignment/convergence.) However, with time and experience, we should be able to say a firm bye, Felicia to (most) regulator-specific hoops in global programs.

There are already some tools in place that the industry and regulators can and should be using to achieve alignment (e.g., parallel scientific advice), especially when it relates to something as potentially perilous as the potency assay. Though we hear little to nothing about it, the FDA, EMA, and Health Canada supposedly also have regular meetings as part of the ATMP Cluster to discuss and, hopefully, overcome substantial scientific differences. (After this Pfizer potency assay news, a status update on this organization would be a good thing to have.)

An “efficient” regulatory paradigm will be nuanced and multifaceted, but we can all agree it should not require drug makers to meander in search of country/regulator-specific data. Eliminating these twists and turns will require the same amount of regulatory coordination, collaboration, (intellectual) athleticism, and precision as Cinderella’s sewing mouse at minute 2:12, who knows to duck at the exact instance the needle comes back through the fabric.

If cartoon bluebirds and mice can be that in sync, the brilliant minds at the regulatory bodies should be able to achieve such feats when evaluating assays, too.