Changes in Drug Development With Richard Pazdur, MD

Welcome, everyone. I'm Dr. John Whyte, chief medical officer at WebMD and you're watching "Cancer in Context." Today I'm delighted to be joined by someone who needs no introduction. Dr. Richard Pazdur is the director of the Oncology Center of Excellence at FDA, and for 20 plus years, has decided which drugs are approved or not approved. Dr. Pazdur, thanks for joining me.

Well thank you, John, for having me. It's a pleasure.

You know I pointed out you've been there 20 plus years. When you started, you were widely criticized as you were withholding cancer drugs from the market. Now 20 plus years later, you're held as a model, literally. And they've created an Oncology Center of Excellence to learn best practices. So I have to ask you, Dr. Pazdur, did you change or did drug development change?

A little bit of both. But I think the major influence has really been the change of oncology drugs. The drugs simply gotten better. Let's just face it. Before we were talking about response rates of 7%, 8%. Now we're talking about drugs that have response rates of 50%, 60%, 70% in some patient populations. I think you have to think about how oncology drugs were developed in the early days of oncology and that spread throughout, really to the start of this millennium until really the poster child of targeted therapy, Imatinib, came into existence in our knowledge that we can target-- have druggable targets basically here for relatively uncommon tumors.

So before in the old days, we used to, what I call develop drugs on the basis of a roulette wheel of drug development. We used to find drugs that had some anti proliferative activity in the Petri dish so to speak, and then do a series of phase one studies looking at maximum tolerated doses. And then through this roulette wheel of, let's do a study in breast cancer, lung cancer, GI cancers, to see if we have activity. And then if there's some glimmer of activity then we'll develop the drug in that disease.

Well that's like looking for the proverbial needle in the haystack so to speak. And when Imatinib came out in the early part of this millennium, I believe it was 2002 or so, really we had a targeted drug that produced unprecedented response rates. And really that was a hallmark of what was to come basically through the next 20 years so to speak in the area of medical oncology. So that's the targeted approach to cancer therapy.

There's also been a revolution in tumor immunology. Before, in my early career, tumor immunology was looked at kind of as black magic, as witchcraft. Now it's accepted. The PD1 drugs, the checkpoint inhibitors, CAR T cells, have really revolutionized basically the way we look at cancer. And personally, I believe that these, immunological approach, really, really holds the key of how we will address cancer in the long run.

So what's left then? [LAUGHS]

Well, there is a lot of work here, a lot of work. And I think it would be-- I would be remiss in saying that-- we've made advances and I to make sure people understand this, but there are really diseases where we have not made advances. I think one of the most rewarding things in my career. And here again, I've been an oncologist now for almost 40 years, is to see diseases where we basically had no therapies and that have been revolutionized and where people are looking at remarkable advances in their disease.

They may not be curative in the advanced disease settings. But when these therapies are introduced in the adjuvant setting, in earlier disease settings, they potentially offer the opportunity for cure. And let's just go over some of those. When I started in the early days, melanoma was basically, metastatic melanoma, had very little therapy. The drug was DTIC, which I labeled as basically a toxic placebo, and as BRAF inhibitors. Then we have the immunological drugs, both Ipilimumab and other checkpoint inhibitors, and the PD1 drugs that came into play here.

They've been introduced into earlier disease settings, that only the adjuvant setting, but potentially now neoadjuvant settings that we are exploring. Lung cancer has been completely revolutionized. OK? When I started in the field, small cell lung cancer, non-small cell lung cancer. Now we've divided the non-small cell cancer into a proliferation of small molecular subtypes, where probably you don't have to do randomized studies because the response rates are so high that people won't go on a randomized study comparing them to chemotherapy, standard chemotherapy, because you're looking at response rates of 20% or 30% versus 50% or 60% and equipoise won't be maintained in that clinical situation to allow randomized study looking at response rates, looking at survival rather.

But you also are looking at additional outcomes nowadays. Something that you and I talked a lot about is patient reported outcomes. How do we measure what's clinically meaningful to patients? That's still a work in progress. Would you agree in terms of [INAUDIBLE]

And I think that's vital. In the Oncology Center of Excellence, we have a whole entire really core group of people that are working on this whole area of patient reported outcomes. I think who is better to assess how a therapy is doing than the patient themselves? And even the way we really measure adverse events, toxicities of drugs, should be coming from the patient directly rather than a third party, a nurse, or a doctor interpreting what the patient says. So we're really working on patient reported outcomes rather in terms of evaluation of toxicity. And also looking at efficacy.

Some of the issues here however, are obviously you need blinded studies to make these credible. Frequently they don't exist in oncology because of the differential toxicities of different drugs in different arms of the studies in randomized studies. But I think these will become more and more important. And we're looking at other endpoints, minimal residual disease, different pathological complete response rates when the drugs are being introduced earlier in diseases. So we're really open to a wide variety of endpoints.

But again, when I started oncology, the dogma was to get a drug approved, you needed two randomize studies and both of them had to show a survival advantage. End of discussion. We would not be here in oncology if we just accepted that dogma and did that change. And we had to be realistic that there are other endpoints that are clinically meaningful to patients. For example, when a tumor shrinks by 50% or by a set amount of a percentage that is determined in response rate criteria, that is benefit to most patients.

If you go in to see a doctor and your doctor says, hey, you know, your tumor shrank dramatically here. To say that that's not important to a patient is rather disingenuous. When a patient has rapidly progressive disease, if you slow that rapid progression and we [? measure the, ?] for example, time to progression or progression free survival, that's important to patients. They may not be cured of their disease, but if they have a rapidly progressing disease and you can buy them time without the disease progressing or buy them time so additional therapies may come into being, that's important.

And we've seen this in some disease, John. For example, in multiple myeloma, when I started the field the only drug that was available for my entire career was basically melphalan and prednisone. That was it. That was it. Then we had the introduction about 10 or 15 years ago of pertuzumab and then a plethora of drugs too numerous to mention with different mechanisms of actions. The life expectancy, when I started, a patient with multiple myeloma was about two years and now it's in the range of about 10 years.

And when one considers the age group, this being a disease of the elderly, that's a significant buying of time here so to speak. And these drugs, their advantage, none of them were shown to have-- or few of them were shown to have survival advantage, is adding them on in sequence or adding them in combination that really made the entire thing possible so to speak.

So lots of success, but still some areas where we need to have improvement, certainly an area of diversity. And let's be honest, cancer trials are different than diabetes trials if you fail standard therapy in diabetes, there's lots of treatment options that you have. In oncology, if you fail standard therapy and you don't enroll in a clinical trial, your options can be severely limited. And we know for new molecular entities that the percentage, particularly of African-Americans, is often in the single digits as a percentage.

Sometimes to be fair, they're in the single digits in actual numbers of people in the trial. So how do we address the issue of lack of diversity in cancer trials? You and I have talked about that in terms of proportionality and representativeness and variability of drug response, but what progress are we making? Because when people look at the numbers and they say, breast cancer and prostate cancer, we're talking maybe 5% are people of color. So how do we manage it?

It's a drug company issue. It's an FDA issue. It's a societal issue. It's an international issue. And I think you have to take a look at some of the root causes. Number one, most of the clinical trials that are done for drug regulation are international in scope. And only about 20% of the patients come from the United States.

Cancer trials, in oncology. And it can vary 70/30 sometimes and 60/40, but most almost all years it's mostly the rest of the world. In those areas of the world that typically don't have the diversity that we think of. It's primarily former Eastern Europe.

A large number of patients come from Poland, the former Soviet republics, et cetera. So we're already starting out with a portion of the pie, so to speak if one takes a look at the entire enrollment center, a section that comes from the United States. And here again, we could do a better job at enrolling those patients in the United States.

We have a project now at the FDA called Project Equity within the Oncology Center of Excellence where we're really aiming at discussing this on a real time basis with companies as they come in, before they start the trial, before they start the trial, what is their plan for increasing enrollment? What efforts are they taking to get African-Americans, the Hispanic population, the Native American population?

When did that start? That's new. That's exciting.

It started within the last couple of months, really as a result of some of the social upheaval that has existed in this society in the spring and early summer here. But it was something that we were very cognizant of and wanted to really have a major impact on. So Project Equity exists. And I want to spend some time on that, because I think it is important.

Number one. So we're talking with the companies what their plans are before they start the trial. Because once you start a trial, everything's out of the barn so to speak. It's hard to get control of everything. Then, if they don't have proper enrollment, and here again we can't delay a drug approval. That would hurt everyone so to speak. And I don't think anyone would be in favor of that. Should we ask for some post-marketing studies to be done in vulnerable populations?

And that could include, just because of social equity, or it could be because we feel that there may be a biological difference in the disease. And some of these might be in multiple myeloma, prostate cancer, et cetera. So these post-marketing studies could simply be single arm trials where we get additional experience and look at response rates in that population. It could come from real world data. It could come from registry data. But that's something that we are particularly interested in.

There's a bigger picture issue here. And that is one that we're taking and involving with another project called Project Community. And a very good friend of yours, Rhea [? Benlaky, ?] is in charge of that project. And basically that is to bring in the other cancer centers and have discussions with them and the community on how to increase patient enrollment. So we've been going out and having conferences in inner city neighborhoods, in major cancer centers that serve these inner city areas, as well as rural areas.

I think we have to be cognizant that it is not just an inner city issue. It involves basically multiple stakeholders. And I do want to emphasize, it is not only the African-American population, it is also the Hispanic population. And the COVID pandemic has put a particular spotlight on those and in addition, the Native American population that has the highest death rate with COVID.