Print BCTV: Breaking Through FDA's Toolkit -- FDA's Woodcock, Pfizer's Harvey assess Breakthrough drugs progress

Breaking Through FDA's Toolkit

Transcript of BioCentury This Week TV Episode 144




Dr. Janet Woodcock, Director, Center for Drug Evaluation and Research, FDA

Brian Harvey, Vice President for US Regulatory Strategy, Pfizer






Dr. Richard Pazdur, Office of Oncology Drugs, FDA

Dr. Robert Temple, Director of the Office of Medical Policy of FDA's Center for Drug Evaluation and Research / Acting Director of the Office of Drug Evaluation I (ODE-I)


Johnson & Johnson


American Society of Clinical Oncologists

Friends of Cancer Research



Steve Usdin, Senior Editor




STEVE USDIN: Can regulatory innovation open the floodgates for important new medicines? The nation's top drug regulator gives the inside story on FDA's breakthrough drugs program. And a senior executive of a global pharma giant discusses what it means for patients and the drug development landscape. I'm Steve Usdin. Welcome to Bio Century This Week.


FEMALE NARRATOR: Your trusted source for biotechnology information and analysis, BioCentury This Week.


STEVE USDIN: A year ago, Congress told FDA to create a new system to speed the development of medical breakthroughs. Six months ago, on BioCentury This Week, Janet Woodcock, FDA's top drug regulator, predicted that few drug candidates have the kind of dramatic effect to qualify as a breakthrough.


JANET WOODCOCK: Well, we hope that everybody develops drugs they think are going to be breakthroughs but we know that many are called few are chosen and in fact, very few end up being breakthroughs.


STEVE USDIN: It turns out biotech and pharmaceutical companies have been developing more potential breakthroughs than expected. As of June 1st, FDA had granted 19 breakthrough designations, 38 applications were pending. This week, BioCentury starts a special two-week examination of breakthrough therapies. We'll start by getting Dr. Woodcock's assessment of FDA's progress to date.


Then we'll hear the corporate perspective from a top regulatory executive, Pfizer's Brian Harvey. And next week we'll hear from three companies that have received breakthrough designations and learn how these therapies could transform the lives of children with a devastating bone disease and patients with lung and blood cancers.


STEVE USDIN: I'm pleased to be joined again by Dr. Janet Woodcock, Director of FDA's Center for Drug Evaluation and Research. Dr. Woodcock, what is a breakthrough drug? And what does it mean for patients and for companies, for FDA, when a drug is designated as a breakthrough?


JANET WOODCOCK: Well, breakthrough drugs well first of all, they're investigational drugs. In other words, they're not approved and out on the market. Number two, they're intended to treat a serious or life threatening condition that doesn't have really acceptable alternative therapies. And number three, they've shown preliminary clinical evidence -- in other words, evidence in people -- that shows they may have a significant fact that's beyond the current treatments that's medically significant and important.


STEVE USDIN: And so that's kind of what a breakthrough is. And how does FDA make its evaluation. It's a little bit mysterious to people. You've evaluated -- you've given more than 19 designations to companies and said your products are breakthroughs. What were the criteria that you used?


JANET WOODCOCK: Well, we try to go to the criteria that are in the statute that describes the breakthrough. First of all, it is a serious and life threatening disease. It lacks good therapies. And basically all the applications we've got have been in that realm.


But then the preliminary clinical evidence has to be medically significant. In other words, we want it to be above the kind of treatment effects we've seen before in that disease -- and well above, not just maybe 2% more than the control or a few patients where it looks like it may be better or something like that.


STEVE USDIN: And then can you give some examples of what has happened or will happen as a result of a company getting one of these breakthrough designations? What's different that wouldn't have happened if they hadn't gotten it?


JANET WOODCOCK: Certainly. Well, one thing we don't want to happen is that a drug that is designated as a breakthrough in early clinical, maybe early phase II data -- looks very, very promising. We don't want people to just go off and business as usual. We're going to do a lot of phase II trials and eventually go to a phase III trial.


And several years later, we'll find out the answer. We want to work with the company to figure out the most efficient way to figure out if that early clinical data, that preliminary evidence, is actually real. So we'd like to repeat that in some way in a robust way that shows that actually is the effect of the drug. And once that's shown, if the side effects are acceptable, then the drug should move toward approval.


STEVE USDIN: So really what that suggests, and I think it's something you've been talking about for a long time, is getting away from this idea of phase I, phase II, and phase III, and really collapsing that. What does that mean for patients? What does it mean for FDA to get away from that traditional model?


JANET WOODCOCK: Right. Well, people who have a serious disease, say, if you have a serious disease -- it may be life threatening, your life may be shortened, your treatments that you're using are not working are not satisfactory-- you really don't want to wait seven years till every T is crossed and I is dotted until you get another therapy that you could try. We understand that.


Also you may not want to be in a long placebo or standard of care trial, where you may not get the drug that seems to be the best drug for your condition. So we want to have a process, a development process that is more or less abbreviated, but is designed to give out important information. Is this drug really what it looks like to be in this early preliminary clinical information?


STEVE USDIN: Something that's really interesting to me, also -- so we talked about this when the law was first passed, and I asked you how many drugs were likely get to breakthrough status. And you said basically, many are called but few are chosen. It's not going to be very many -- it's been a awful lot. Have you been surprised by it? And is it a temporary blip, or are we going to see more and more of these breakthroughs?


JANET WOODCOCK: Well, I don't know. I can't say firmly that it's not temporary. But I suspect that this is a type of drug development that we're going to see in the future, probably driven by targeted therapy, which many of these breakthroughs have been targeted to a specific group of patients.


STEVE USDIN: So then when you say targeted therapy that means that there's some kind of marker, maybe a gene mutation or something that indicates that that is the right patient to get that drug. In general, this high efficacy that you're seeing in breakthrough drugs, is it a result of the fact that these drugs are really much better than drugs in the past? Or is it just that they're targeted so the right people are getting them?


JANET WOODCOCK: I suspect it's because they're targeted. In other words, we used to take an empirical group, say, of cancer patients. Say, they had some kind of histology of lung cancer. And they would get standard care or standard care plus this new treatment. Now we know that with these targeted therapies, only a subset could respond. And so we're focusing on that subset that has a chance of responding. And then we see a much higher rate of response.


STEVE USDIN: And that allows you get results also sometimes from Phase 1 trials which you couldn't before. We're going to continue our conversation with FDA's Janet Woodcock about breakthrough pathways in just a moment.


FEMALE NARRATOR: Next week, how Alexion's biotech drug could change the lives of children disfigured by an ultra-rare genetic disorder. You're watching BioCentury This Week.




STEVE USDIN: We're talking with FDA's Dr. Janet Woodcock about breakthrough medicines. Dr. Woodcock, there's a difference between a breakthrough that creates a dramatic effect if it's transitory and a cure or a functional cure, especially in cancer. A lot of the breakthroughs that you've approved there we know that there's going to be resistance that's going to develop. They're not going to be cures. How do we go from these dramatic effects to cures?


DR. JANET WOODCOCK: Well, we have to first focus on the fact that's where we want to go. OK, so we ought to be thinking about prolonged remissions, prolonged complete responses and cures and thinking about how to get to there. That's why FDA several years ago issued the guidance on combinations of investigational drugs, because it's clear in many cases, it's going to take combinations. But my philosophy is that we need to get these targeted agents out there -- particularly one's that are better than current therapy -- and then start rapidly iterating, combining them, elucidating the mechanisms of resistance through science -- because we can do that rather rapidly now with sequencing -- and then add additional agents on until we get to cures. If you talk to Bob Temple about long ago in testicular cancer, that's basically what they did. They kept adding treatments on until they got cures to that disease.


STEVE USDIN: So that's kind of an answer also to people who criticize drug companies, criticize FDA, and say, well, look there are these new cancer drugs that are coming on the market. And they extend life for whatever period of time it is -- four months, six months, a year. Why are we doing this kind of thing? And basically what you're saying is it's the first step.


DR. JANET WOODCOCK: That's right. If they extend life, that's better than not extending life. But it isn't good enough. We have to really drive toward curing these or getting them into prolonged remissions. But we have to have the tools. It's clear the cytotoxic agents we have now are not the tools for most of the solid tumors.


STEVE USDIN: So, and again, sticking with cancer, at the recent meeting of the American Society of Clinical Oncology, there was a lot of excitement coming out of it. And some of the people that I talked to coming out of it said that they are foreseeing a wave of new approvals of cancer drugs, breakthrough drugs. And that they could imagine times in the near future where there might be one every other week being approved by FDA. Is that realistic, or is that too much excitement?


DR. JANET WOODCOCK: I think it's realistic. We can only hope that occurs. We have to realize that whole wave, is this -- the first, we're getting a whole new toolbox for oncologists. And they're going to have to be combined in a way along with molecular diagnostics, maybe functional assays and so forth, in a way that we can really drive toward better outcomes for people with cancer.


STEVE USDIN: And is FDA -- do you have the resources, the infrastructure, to deal with this kind of a huge increase in the number of submissions and approvals?


DR. JANET WOODCOCK: Well, it's going to be a strain on our resources, obviously. But because it's such good news, I think we can move toward trying to deal with that. Even regulating the manufacturing and making sure that the drugs are of adequate quality, all these new investigational drugs, and especially as they move very rapidly through the development process is a big challenge. So we are looking at ways to refine our organization and do some other things so we can be more efficient.


STEVE USDIN: So one of the other challenges with breakthrough drugs is that if you're going to be getting drugs onto the market, as you said, as quickly as possible to get them to the patients who really need them, then they're going to be coming to the market without all of the information that they might have come to market if it had been a more slow development process. How is FDA and how's the medical system in general going to incorporate the new information that's going to come up about drugs after they're already on the market?


DR. JANET WOODCOCK: Well, it's been a perennial problem. When we put a drug on the market for the first time, most clinicians absorb that information around the drug. So if we say it's a targeted drug, should be used in this way with this companion diagnostic, usually that will happen. But as more knowledge evolves, maybe indication widens, they are more diagnostic tests that should be done, then there's a diffusion of that knowledge in a way that isn't satisfactory, I think. And we're really going to have to work on that.


STEVE USDIN: I want to take another step back on breakthroughs. One of the ways that people, especially investors, have interpreted the breakthrough designation is that this is a stamp that says that FDA is going to approve this drug. Is that realistic, or is there a greater chance that FDA is going to approve a drug or that it's going to be approved on a first cycle if it gets breakthrough designation?


DR. JANET WOODCOCK: Well, I don't think I can prognosticate the future. We know that we have seen preliminary results in the past that were spectacular. And then further investigation shows that drug is really a dud. All right? So that's going to happen. The designation is not an approval. Designation says simply that current clinical information we have on that drug looks really, really good. And if it's replicated, if it's duplicated, and there isn't some horrible side effect that emerges -- and it would have to be pretty bad, probably -- then that drug could be approved.


STEVE USDIN: One of the things that was in the same law that created the breakthrough pathway was language telling FDA to expand the use of something called accelerated approval and to expand it out of the areas where it's traditionally been used, which is HIV/AIDS what it was invented for and cancer where it's been used quite extensively. First, can you describe what accelerated approval is? And what the progress has been in expanding it outside of cancer and HIV?


DR. JANET WOODCOCK: Sure, well, accelerated approval is approval on a surrogate that hasn't necessarily been shown to correlate with clinical benefit in a totally reliable way.


STEVE USDIN: So, an example would be in HIV, it was measuring viral load of HIV and blood. That didn't show whether the patient was getting better or not. But there was an idea that if you measure that viral load, you would know -- if you suppressed it -- that you'd know the patient was going to get better.


DR. JANET WOODCOCK: That's right. There is a pretty good link. And here, the link is reasonably likely. We would approve it on something that we think is reasonably likely to predict that clinical benefit, but not proven. And so the statute asks us to consider also intermediate clinical endpoints, say, if you have cancer and your tumors shrink, maybe that's a surrogate. But maybe you have some other improvements that would show that perhaps you wouldn't die as quickly or have serious morbidity. And we have taken that into account seriously.


And, for example, our recent guidance on accelerated approval in Alzheimer's disease is an example. Now usually in Alzheimer's disease, we want cognitive and functional endpoints. We want to see the benefit on both of those versus no treatment. And those are for symptomatic treatments that we have approved. But it's clear that for Alzheimer's disease, we're going to have to treat people earlier because the burden of disease in the brain is very great before people even show symptoms. So we said OK, what if we use a measure of cognitive impairment that's very subtle and actually doesn't reflect the clinical function of the person, but a very subtle measurement. And if you can show that you have prevented that from declining, say, then we would do an accelerated approval and you'd have to show them that prevented progression to dementia or something later, more serious manifestations of Alzheimer's.


STEVE USDIN: So that's a good example also of something else, which is it's one thing to set that what the criteria for getting accelerated approval is. It's another thing to be able to meet it. It's not as if companies have got drugs on the shelves that could meet that criteria right now and they hadn't been submitting them to FDA, because you didn't have those criteria. We don't have drugs that can do that?


DR. JANET WOODCOCK: Right. Now the theory is though that if we provide a pathway to get on the market sooner and more realistic, maybe intervene in Alzheimer's before your demented, or maybe a better chance of succeeding in treatment and will attract investment into that field and attract development, because there is a viable pathway to market.


STEVE USDIN: Well, we're going to be back in a moment, with a big pharma perspective on the breakthrough drug pathway.


NARRATOR: Next week, how a Novartis drug called LSK378 produced dramatic results for patients with lung cancer.




NARRATOR:  Now, back to BioCentury This Week.


STEVE USDIN: We've heard FDA's vision for the breakthrough drug pathway. What does big pharma think? I'm pleased to be joined by Dr. Brian Harvey, Vice President for US Regulatory Strategy at Pfizer. Dr. Harvey, Pfizer applied for breakthrough status for a breast cancer drug candidate recently and received it. Can you tell me what the drug is and why you applied for breakthrough status? What do you expect that to change?


DR. BRIAN HARVEY: Well, first of all, thank you for inviting me here today and I'm happy to report that in April of this year, Pfizer received breakthrough designation for the investigational product Palbociclib. And it's a selective inhibitor of the cyclin kinases two and six, and there's great hope that there's going to be a benefit in treating patients with breast cancer. And so, we received that designation. We're working with FDA, and currently, we're in the midst of discussions on what actual data is going to be necessary for us to accumulate to submit to FDA for their consideration for product approval.


STEVE USDIN: So you have been on both sides of this. You've spent more than a decade at FDA as a medical reviewer as the head of a division. And now, you've got a lot of experience in industry. What do you think is going to happen that could be different as a result of getting this breakthrough designation?


DR. BRIAN HARVEY: Well, first of all during my time at FDA and especially when I was a division director in CDER, I was always pleased to have various tools in order to use them as part of the regulatory review process and development process for products, for both drugs and biologics. And so, breakthrough designation now gives the reviewers and the division and office managers at CDER an additional tool for them to use in order to help evaluate products and, of course, ultimately, it's product approval that's going to help patients. But that development time can be years. And so, having another tool that can be used in order to speed the development in order to accumulate the appropriate data to show benefit risk, and if you have that appropriate balance for, ultimately then, for approval for patients to use it in a long term.


STEVE USDIN: So one thing a lot of investors have interpreted breakthrough designation to mean, that it's much, much more likely that a drug will ultimately get approved. Do you think that that's a reasonable supposition?


DR. BRIAN HARVEY: Well, I think the concept behind it is to choose ahead of time, based upon certain specific criteria, of how it's anticipated the trials will come out. And so, it's a combination of not only the unmet medical need, but also the strength of the data, the strength of the efficacy signal and then, by trying to make that determination ahead of time, then focusing the appropriate resources in order to facilitate that communication. Because, as we know, good communication between a sponsor and the FDA is key. It's a pathway that we really need to work on, because even a good product can have issues during a development program if you make certain assumptions up front that don't end up to be true.


STEVE USDIN: So one of the aspects of the breakthrough designation is that it's intended to get drugs to patients more quickly, especially, patients with serious unmet medical needs. There's another set of procedures the FDA has that people call compassionate use to do that. A lot of patient groups say that those set of tools aren't working as they should. What's your sense about that? Do they work like they should, or is there a need for a revamp there?


DR. BRIAN HARVEY: Well, in the popular language, compassionate use is often used. But as you know, in the FDA regulations, there actually are many different mechanisms that have names other than compassionate use, so treatment INDs, individual INDs. And it's interesting that just this past month, FDA released a draft guidance document outlining all of these different mechanisms. Now, the mechanisms are not new, but the timing is interesting that now they're re-looking at these traditional mechanisms to get product to patients. And of course, it's prior to a product approval. And so, it's really intended to be short-term, as a bridge.


STEVE USDIN: So, just very quickly because we're running out of time. Yes or no? Do you think that those compassionate use tools as a whole are working as they should, or is there a need for a re-look at that?


DR. BRIAN HARVEY: Well, I think in the oncology space under the direction of Dr. Richard Pazdur it's very appropriate to have a compassionate use type program between the time of an application submission and an approval. I think we always need to be wary in other divisions if that time frame is too long, because it is intended to be a short bridge not a long bridge.


STEVE USDIN: OK, thanks. We're going to continue the discussion with Pfizer's Bryan Harvey in just a moment.


NARRATOR: Next week, how Johnson & Johnson is creating a pipeline of breakthrough candidates for cancer.




STEVE USDIN: We're back for some final thoughts about pursuing breakthroughs with Pfizer's, Brian Harvey. Brian, you were talking just before the break about compassionate use. And you were saying, well, that's it's useful if it's used across FDA, across FDA equally. What did you mean about that? Is there any issue about the consistency of what different parts of FDA do both in compassionate use and on other programs that are intended to speed drug development?


DR. BRIAN HARVEY: Well, of course, it's always a challenge, because the different disease areas have different impact on patients. There are different perceptions of benefit risk. I think from the breakthrough designation standpoint, having those extra tools aren't very important. But I think we've seen that over the years that some divisions are more likely to use certain tools than others.


And I think in the oncology office with Dr. Rick Pazdur, he's just recently won an award from the Society of Clinical Oncology for some of his work in the area, he uses those tools. And some divisions, the tools don't get used. And as you know, if you don't use a tool it gets rusty. So having tools available in order to have that as part of their ability to act on certain indications for certain therapeutic areas, I think it's important.


STEVE USDIN: So one other thing. You talk about tools. There's this proliferation of tools or pathways at FDA. You almost need a scorecard to keep them straight. There's accelerated approval, fast track, orphan designation, priority reviews, breakthrough, and there's talk about creating a new one, special medical use. Does it make sense to have this proliferation of special little tools that are intended to speed different kinds of drug development? Or, does it suggest that we need a rethinking of the drug approval and oversight system?


DR. BRIAN HARVEY: Well, I think we need to really look at how the tools are being used, see how they're being used in oncology, see if the tools that we already have have applications in other areas to be more widely used, and then, only after that careful consideration, decide on whether or not we need an expanded tool kit in order for approval.


But it is good to have some flexibility as you're moving forward. And it really stresses the importance of early communication between sponsor and FDA at that pre-IND, that early development phase. The end of phase II meeting is so pivotal in having those discussions to make sure you're on the right pathway. Because although it's a drug review process, to help the patients, you need to have it be a drug-approval process.


STEVE USDIN: Very quickly. One of the things that FDA is going to be doing is setting out guidance about this breakthrough designation. What are you going to be looking for? What are the things where there's uncertainty, now, that you'd like to see some certainty around in that guidance that's going to help drug developers?


DR. BRIAN HARVEY: Well, I think some added clarity when there are discussions about additional communication. What type of communication? Would it be in a form of a face-to-face meeting? Will it be a written communication? Where will it be in the process? There are certain key times when you really need to get an answer to something right away. That's the Type A meeting with the 30-day turn around, and being able to get that timely advice when you need it can be so critical when you're developing a product.


DR. BRIAN HARVEY: All right, thanks. That's this week's show. I'd like to thank Janet Woodcock and Brian Harvey. Please join us next week when BioCentury features case studies of breakthrough drugs under development by three companies: Alexion Pharmaceuticals, Johnson & Johnson and Novartis.


Remember to share your thoughts about today's show on Twitter. Join the conversation using the hashtag#biocenturytv. I'm Steve Usdin. Thanks for watching.


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