Gene and T-cell therapies hold promise for treating rare and debilitating diseases that in the past had no treatment options. Yet, the time to plan and execute clinical trials and gather the evidence needed for regulatory agency approval makes those suffering from the diseases being targeted wait many years for treatment.

Luxturna, the first-ever gene therapy to treat a genetic disease causing blindness, developed by Spark Therapeutics, and Yescarta, the first CAR T-cell therapy approved for adults with certain types of non-Hodgkin lymphoma from Kite, each took about nine years from Investigational New Drug (IND) application to product approval.

[RELATED: For information on the FDA Drug Review Process, check out our Checklist for interacting with FDA.]

Checklist: Interacting with FDA During Drug Review Process

At the ISPE Biopharmaceutical Manufacturing conference held virtually in early June, FDA Center for Biologics Evaluation and Research (CBER) Office of Tissues and Advanced Therapies (OTAT) Director Wilson Bryan shared his vision of how that nine-year time might be reduced to three or four years.

The Traditional Drug Development Process

Bryan began by discussing the traditional drug development process. “First of all,” he said, “there should be some understanding of the disease process that you want to target. Then, what is the target? What is the aspect, the pathophysiology of that disease, that you can identify that you think is amenable to interventions and target identification?”

Next is the process of drug discovery to find a product that seems to act on that target. Ideally, this is a critical step in the pathophysiology of the disease. After drug discovery comes preclinical studies, particularly animal studies that look at the principal and, ultimately, guide the design of subsequent clinical studies.

And, then clinical development (Figure 1). Clinical development has a Phase 1. Traditionally, this refers to a study to assess safety, find a maximum tolerable dose, and, maybe, obtain a preliminary look at activity.

**FIGURE 1 | Traditional Clinical Development**

The results of the Phase 1 study help design Phase 2 studies.

In Phase 2, you sort out the dose, the route, the regimen, population, and endpoints.

The results of the Phase 2 study are used to design the Phase 3 study, which hopefully will gather the evidence of effectiveness and safety to support a marketing application such as a biologics license application (BLA).

A Home Run for Product Approval

Bryan likened clinical trial phases 1, 2, and 3 and product approval to the four bases in baseball (Figure 2).

“One way to play baseball is for the player to hit the ball and go to first base. This is like Phase 1. Then the player stays on first base until somebody else hits the ball, and then that first player can move to second base. The player on second base now has to wait for somebody else to hit the ball so that maybe they can go to third base, and if they are lucky, get home.”

“This is like Phase 1, Phase 2, and Phase 3. If you have watched baseball you know it can be very slow and it can be very stressful to watch. But it does not have to be this way. There is a different way to play baseball, and that is to hit the home run. The idea of hitting a home run is that you can do all the bases at once.”

A Home Run in Gene Therapy Development

With the scientific advances that have been made in gene therapy, “we should be thinking about doing a Phase 1 study that is designed so that it can gather the evidence of safety and effectiveness that is necessary for marketing approval,” Bryan maintained. “So, the Phase 1 study can also be the Phase 3 study and it can all be done at once. Now, how do we do that? How do we hit home runs in drug development instead of doing Phase 1, 2, 3?”

Step 1: Preparation

The first step is preparation—early collaboration between scientists and clinicians. “Too often in gene therapy and in other areas there is a scientist in a lab somewhere working in isolation on a gene therapy. Particularly with the advent of the Human Genome Project and related initiatives there are thousands of labs around the world looking at specific genetic defects and thinking about how they are going to fix them.”

“These scientists need to be talking to the clinicians,” Bryan emphasized. He recommended that they collaborate early in their projects, and that when the preclinical studies are beginning that is the time to draft the design of the clinical studies. Going through that exercise of drafting the design of the clinical studies when the preclinical studies are being done allows you to realize what sort of endpoints you are going to need and develop.

He suggested asking what sort of natural history data you need that you do not have yet, noting that designing and conducting the natural history studies that will support subsequent drug development can take years. He pointed out that Zolgensma—the Avexis/Novartis gene therapy for treating Spinal Muscular Atrophy (SMA)—had the benefit of a natural history study that had been done a decade earlier.

Step 2: Play as a Team

Play as a team. “This should be obvious,” Bryan commented. “Efficient drug development requires collaboration of the scientists, academic investigators, sponsors, funding organizations, patients, advocacy groups, and regulatory agencies. Folks have to talk to each other and start talking to each other early in the process.”

Step 3: Try to Hit a Home Run

Try to hit a home run. Design the first-in-human clinical trial to provide evidence of effectiveness, such as including randomization in the Phase 1 study.

“The science has advanced to the point that the scientific rationale for many of these gene therapies is compelling, and we are seeing products that have large magnitudes of effect. If you look at the thousands of drugs that are approved and on the market, many of them, I am going to say most of them, do not do a whole lot.”

Many gene therapies with compelling science have the ability to change lives and save lives. And they do not require huge clinical trials. But they do require well-designed, rigorous clinical trials, the OTAT director said.

Resolve Manufacturing Issues Early

Keeping in mind that the first clinical trial might be the Phase 3 trial for marketing approval, it is essential to resolve manufacturing issues as much as possible before the first-in-human clinical trial, Bryan commented.

“I realize that not everything can be resolved before going into humans. But too often we at the agency see products where the thinking seems to be, ‘I am going to make changes in manufacturing, but I am going to make them in Phase 2, or I am going to make them in Phase 3. I am going to take care of all that later.’ Don’t do that.” Plan on the first trial being sufficient. Get the manufacturing in line early.

“Unfortunately in gene therapy, we are seeing products where we have the clinical evidence of effectiveness—the manufacturer, the sponsor, has shown that this product helps patients—but because of manufacturing issues, it may be another year or more before they have the manufacturing in line and can come in with a BLA to get approval,” Bryan pointed out. “The manufacturing issues are holding up approval of these products. That is because not enough attention is being paid to manufacturing early on and with the mindset that the first trial might be good enough.”

In some cases, the first-in-human study can be sufficient. I want to encourage folks to do rigorous Phase 1 trials and try for the home run.

Q&A Focuses on Timeframes, Analytical Challenges

The Q&A after Bryan’s presentation focused on the amount of time he anticipated approvals might take place if a company “hits a home run” and the challenges of tying down the manufacturing process and analytical methods early in product development. His transcribed remarks follow.

“A company will not be able to resolve all the manufacturing issues prior to Phase 1. But there will be some questions that are hopefully going to be answered with the data gathered in Phase 1. It is a bit of a moving target.

“You are gathering data that you hope will be good enough to identify the critical process parameters and product characteristics. If you are hitting a home run, the Phase 1 data will be sufficient, not just for clinical purposes, but also will give you the characterization that you need for marketing approval.

“Of course, just as there is no guarantee that the Phase 1 study will be successful from a clinical standpoint, there is no guarantee that you will get the necessary manufacturing information out of the Phase 1 study. But you need to go into the study with that in mind. You need to start the Phase 1 study with the idea that you are going to gather the manufacturing information that you will need to put the product on the market. Maybe it will work out, maybe it won’t. But if you don’t go into it with that mindset, then you won’t get the data.

“How long should it take for you to hit a home run? What is that going to look like? For the first three gene therapies that were approved—the two CAR T products, Kymriah and Yescarta, and Luxturna—the average development time from when the IND was submitted to marketing approval was about nine years. That is a long time but is not unusual for drug development. However, when you look at the magnitude of the effect size, why did it take so long?

“Part of the problem with Luxturna was the company had to develop an entirely new outcome measure. Now that outcome measure is likely to be used by subsequent manufacturers who are developing products in that space. So that can save time there.

“With Yescarta and Kymriah, these products, although they save lives, are also extremely dangerous products. These are powerful products. They had huge safety issues during drug development that had to be worked out and that slowed down the drug development. We know a lot more now about the cytokine release syndrome and the neurotoxicity that can occur with these products. So subsequent CAR T products, I think, will come along much quicker.

“The field is young. We are learning. We are standing on the shoulders of giants who have gone first. I expect that we will see in the future gene therapies that from the time of the first IND submission to the time of marketing approval is on the order of three or four years.

“An initial study, well-designed, rigorously designed with compelling science behind it could complete enrollment in six months, complete the study in another two years to follow patients, followed by six months to get the data and regulatory approval. I think they could be done in three or four years.

“If you are a patient with one of these bad diseases, that sounds like forever. On the other hand, if the alternative is an average of nine years, that sounds pretty darn good. So, hopefully, we will just keep whittling that down as the science improves and the science of drug development improves, and we will be hitting home runs.”

[Editor’s note: For more on manufacturing issues involving CGT products, read the author’s earlier posts on the topic.]