FDA and the CMC Goalposts: CMC Should Accelerate, Not Curb, Gene Therapy Progress

By Geoff MacKay, CEO, AVROBIO

There’s no getting around it: This has been a challenging stretch for gene therapy companies on the chemistry, manufacturing, and controls (CMC) front. We’ve all seen the headlines of clinical trial and BLA filing delays while companies respond to CMC concerns.

Behind these headlines are real consequences: Patients have had to cope with heartbreaking delays to clinical trials. Manufacturing and technical teams have endured the frustration of being forced to backtrack over ground they thought they had covered. And the stock prices of companies facing CMC-related delays have dropped precipitously.

Given all this tumult, I’m often asked whether the U.S. Food and Drug Administration (FDA) is cracking down on the industry more harshly than expected. Are regulators moving the goalposts? Are they setting unreasonable standards?

I don’t think so. If you look back at FDA guidance on gene therapy over the years, you can see that the agency has always prioritized tight regulation on CMC. It’s a function of their core mission to keep patients safe. The agency issued clear guidance for gene therapy companies more than a decade ago, when the industry was just starting to come into its own, and has updated it several times since, most recently last year. From day one, FDA has stuck to several core tenets, which govern not just gene therapy, but all biologics. (In fact, their origin can be traced to the 1980s, when monoclonal antibodies were first emerging as a cutting-edge field.)

In a nutshell, FDA insists on three overriding principles[1]:

• First, manufacturing protocols and process controls must be clearly deliniated.
• Second, process changes must be explained, documented and tested.
• Third, potency assays must be well-validated and tightly linked to both the drug’s clinical efficacy and its mechanism of action.

None of those principles has changed over time. The bottom line is, regulators want to see that a company has control over its processes and products. FDA has made clear that it’s okay for processes and assays to evolve over time; especially with products as complex as cell and gene therapies, early-stage companies don’t need to have every detail solidified on Day 1. That said, however, every update must be rigorously documented and subject to process and quality controls.  And by the initiation of Phase 3, manufacturing must be phase-appropriate.

In my view, the recent spate of headlines about CMC crackdowns boil down to FDA enforcing its well-established guidance. If there is anything new, it’s that the enforcement has become more visible, and the consequences for industry more serious, because so many investigational gene therapies are moving toward the big milestones eagerly awaited by patients and investors alike, from first-in-human trials to registration trials to BLA applications.

Peter Marks, M.D., Ph.D., director of FDA’s Center for Biologics Evaluation and Research, pleaded in a recent address at the World Medical Innovation Forum for cell and gene therapy makers to take CMC seriously and invest early in analytics that can measure the potency and consistency of their products. "Many times developers get very excited about the fact that their product produces an important effect [and] they don't worry as much about reproducibly making that product,” Dr. Marks said, according to an article in BioPharma Dive.

One Company’s Approach to CMC

In biotech, you quickly learn to expect the unexpected, and I would never have the hubris to declare that we have the CMC issue solved. But I can say that we have taken FDA at their word that CMC is crucial. Since the very first day we founded AVROBIO more than five years ago, we have been pushing ourselves to meet and exceed FDA standards to accelerate drug development.

Our approach isn’t the only way forward, of course, but I hope other companies concerned about CMC can find some useful tips in our approach to building our gene therapy platform, plato®.   

Solving Scale via Innovation

One of our earliest decisions at AVROBIO was to break from conventional wisdom in the industry when it came to manufacturing. There’s an ocean of bias in the gene therapy field for building big (and quite expensive) bricks-and-mortar manufacturing plants. We chose to go in the other direction — and solve scale via innovation. Instead of 150,000-square-foot factories, we rely on portable, automated manufacturing “pods,” about the size of a dishwasher. Because each automated pod acts as its own contained clean room, we have the potential to significantly increase capacity by deploying multiple units side-by-side.

We started with an off-the-shelf unit made by the German firm Miltenyi Biotec and spent three years developing algorithms to deliver drug products that met our specifications. It was a challenging road, but we consider it well worthwhile. Automation is intended to reduce human error, with the goal of producing consistent drug product from batch to batch. Just as important, we believe automation can help address challenging regulatory requirements to reconcile processes across global facilities.

Leveraging Analytics to Help Accelerate Development

Another key challenge with gene therapies is defining product characteristics – essentially, the physical, chemical or biological properties of the investigational drug that impact the therapy’s quality (and, by extension, its safety and efficacy) and thus must be kept within a pre-defined range. Good analytics help you demonstrate you meet those characteristics with every batch.

I’ll be the first to say that product characterization for these highly complex therapies is not an easy task. We have invested a huge amount of time into developing and assessing a suite of potential potency assays. We understand that for complex drugs, potency might not be defined by a single assay and a matrix of multiple assays might have to be deployed. We use these assays – or matrix of assays – to evaluate drug product as we produce it and then correlate those metrics against the relevant clinical data. Our goal is to evaluate multiple assays for their ability to predict efficacy during clinical development, achieve Phase 3 readiness for our VCN and transduction assays for our first clinical program and then leverage these to accelerate the development of our subsequent clinical programs.

A Key Moment for the Industry

At the WORLDSymposium™ in February, Dr. Marks highlighted the opportunity we have as an industry to expedite the development of gene therapies for rare diseases – and really ultra rare diseases – by leveraging the knowledge, validated processes and proven technology we gain with each investigational program we advance. If the gene therapy industry can transfer that knowledge to each new program, we can meet the needs of patients and families living with rare diseases that much faster.

And that, at the end of the day, is what drives us all. As an industry, we have come so far in developing this field and advancing gene therapies that have the potential to be truly transformative for families around the world. We cannot let analytics and manufacturing be the hurdles that trip us up right as we’re about to burst out of the starting blocks.

Done right, CMC development can accelerate clinical development and bring these important medicines to patients faster. Now that is a headline we all want to see.

Geoff MacKay is president and CEO of AVROBIO, a leading ex vivo lentiviral gene therapy company that is developing the first gene therapies in the world for Fabry disease, cystinosis and Gaucher disease type 1, all of which are now in the clinic. None of AVROBIO’s investigational gene therapies have been approved by the U.S. Food and Drug Administration or any other regulatory agency. For more information, go to avrobio.com.