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Medelis: Has the complete phase Ib caught on? Is big pharma adopting this approach?
Dr. Von Hoff: In 2007, at ASCO, when we presented the complete phase Ib approach as a way to get to the randomized phase II more quickly, there were only about 25 people talking about it. Now I get a call once a week and we have six trials running. It makes sense for big pharma because it generates the chunk of information you need at one time, rather than serially, for better decision-making.
Medelis: What happens when the complete phase Ib approach pushes for drug combinations that aren’t approved? Who pays for the drug?
Dr. Von Hoff: If you have good evidence for using an agent in an arm but it isn’t indicated yet, then the sponsor would help pay for that drug for that patient. Or there may be literature indicating that an agent works, but the company hasn’t filed an NDA for an extension. In these cases, you at least have a fighting chance with the insurance company. And even if insurance doesn’t pay, the sponsor has a rationale and incentive for covering the cost of the agent.
Medelis: What’s the FDA’s position on this approach? Have they implemented any new regulations to facilitate it?
Dr. Von Hoff: Each trial is filed with an IND and performed with the utmost safety. In reality, it’s not fundamentally any different than doing six trials in serial fashion.
Medelis: Keeping investigators engaged and interested is critical for any trial. How have investigators responded to the complete phase Ib?
Dr. Von Hoff: Investigators are enthusiastic about this approach. One reason is that patient enrollment is extremely fast; now you have the opportunity to treat almost every patient who walks into the clinic. The patient population is relatively healthier because they’ve received less treatment, which increases the chances of seeing a response in the phase Ib trial. Patients, their families and doctors like it because the patient has the greatest chance of getting a positive effect because, in most cases, the drugs are already approved for their type of cancer. And they’re getting an extra kicker — another agent that might help them even more.
Medelis: Looking ahead a few years, what do you see? Will the complete phase Ib become the “typical” approach?
Dr. Von Hoff: I would say that it’s just another drug development methodology. It doesn’t have to become the standard to have utility. I’m hoping there will be even better ideas down the road. Right now, we know it saves time and effort. You see responses. And I think there’s a lot in it for patients, which is one reason it’s catching on so fast.
Medelis: The focus on combinations seems to be a major shift. It wasn’t so long ago that sponsors were pursuing approval for single agents only.
Dr. Von Hoff: Cytostatic agents are okay by themselves but many types are better in combination. Many of the recent approvals are for combinations, potentially increasing the relevance and need for the complete phase Ib. In the old days, you usually got approval as a single agent and then you would start the combination work.
Medelis: How is the focus on combination therapy changing business alliances among companies that are inherently competitive?
Dr. Von Hoff: There are some pioneering companies who are now establishing overarching agreements to facilitate combining their drugs, including investigational drugs not yet approved. It is a powerful edge for two pharmaceutical companies to work together in this manner. It also gives smaller biotechs opportunities to bridge to big pharma.
Medelis: In your experience, how open have companies been to these possibilities?
Dr. Von Hoff: We do not have any trouble with established agents. Most of the time, the sponsor of the standard agent will supply the drug for a study because it could potentially expand the agent’s utility, and they’re getting the rest of the study free. If a biotech company can get the big guys to supply the agent, then that really cuts down on the cost. Everybody benefits.
Medelis: What would happen if you had two investigational agents in an arm?
Dr. Von Hoff: That would take a lot more negotiation. But let’s face it, if two investigational agents look more promising in combination than either agent alone, why would you not want to collaborate? I think those who don't will be left in a cloud of dust.
Medelis: At what stage in the drug development cycle should a CMO of a small to medium-sized biotech start planning for these potential alliances?
Dr. Von Hoff: Right away, and definitely at the preclinical stage. A CMO should be thinking, what is standard therapy now? What kind of preclinical information will be required to structure one study with multiple arms? This kind of forward thinking can help enormously with funding since you're talking about saving time and money — you're funding just one study — and you don’t have to find the needle in the haystack to get patients on these studies. It generates interest in the molecule because you have responses in various combinations. Once you see a response, you have your evidence for moving forward. It sets you right up for the randomized phase II.
Medelis: So the complete phase Ib sounds like a win-win-win since there is benefit to patients, investigators, and sponsors?
Dr. Von Hoff: Approaching the phase Ib as not just a toxicity trial but also a therapeutic opportunity is actually a quadruple win. CMOs benefit on the business side; they get better data faster, helping to drive fundraising and corporate development. Investigators have an opportunity to make an impact, delivering better care and the chance for a better outcome. And sponsors get answers faster and with less bureaucratic hassle since trial management is streamlined.
Last but not least, the complete phase Ib is an important opportunity to truly help patients. And in the end, that’s the most valuable win of all.
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