FDA Office of Hematology & Oncology Products Director Richard Pazdur, MD, sat down to discuss the state of cancer R&D, Breakthrough therapies, and how his staff pushes to complete those speedy three-month reviews during The RPM Report’s FDA/CMS Summit for Biopharmaceutical Executives in December. Here is a transcript of the conversation, edited for clarity.

Q: Oncology drug development is really hot right now. Over the last couple of years, one-third of the novel drugs that have been approved by FDA are in oncology. What excites you the most in oncology R&D?

Richard Pazdur: What we have now is a greater understanding of the disease process itself and how the immune system reacts to some of these changes. What we are seeing is basically better drugs being developed, more targeted drugs, and drugs based on a more thorough understanding of the malignant disease process and how the body handles that process.

This is about my 30th year as being an oncologist, so I have a perspective that spans from the late 1970s. At that time, general cytotoxic drugs were being developed, and we thought that the whole field would emanate around that. But I think this is more of an exciting time, given that we have a more thorough understanding of the biology of the disease and are actually able to tailor drugs around that.

FDA’s Oncology Office: The Inner Sanctum

Q: Your office is known for some pretty speedy new product reviews. Are there ways that you run your office differently than the other review divisions that help push those through faster?

Pazdur: Yes. While other review divisions might have a mix-mash of various different diseases, we are totally devoted to oncology and benign hematology. So we have a breadth of reviewers in the division – approximately 40 to 50 medical oncologists and pediatric oncologists. It is a very expert group of people that have been working in the field, which makes it a different office than others in the agency.

One of the hallmarks of our review process is that we start discussing an application before it is actually submitted. We’re having discussions internally. We have large meetings on Mondays and Fridays where we invite the sponsor to present various portfolios that are attended by all of the medical oncologists in all of the three divisions as well as our preclinical division. We discuss the weaknesses and strengths of the applications that are coming in.

Soon after the application is submitted, we have what is known as an application orientation meeting. This is something that I started at the agency when I arrived. We ask the sponsor to come in and give us their interpretation of the NDA or BLA. What is their perspective of it?

Now, I assure you, I will hear about all of the problems with the NDA or the BLA from the review staff. It’s like a court of law. Our process provides a perspective of the application from two potentially diverse viewpoints: (1) the sponsor’s viewpoint, which may present a more favorable picture of the NDA or BLA; and (2) the reviewers’ opinion, which may take a much more critical look at the application.

Also during that process, we ask the sponsor to sit down with the review staff to go through where things are located in the NDA or BLA. It used to drive me crazy when a reviewer said, “I spent an entire week trying to find something in the NDA, in this mass of information.” And I said, “Why don’t you just call up the sponsor and ask them where it is? It’s probably self-evident where it is, rather than spending all of this time as a detective, trying to find where it’s at.”

And we’re discussing very early on whether an application will need an advisory committee. Let’s face it, every application has a problem. There’s no such thing as a perfect NDA; there’s no such thing as a perfect BLA. What can we live with? What can we not? What are game stoppers? And how can we relay that very quickly to the sponsor?

Q: With all of that prep work, it sounds like by the time an application is submitted, you have a pretty good idea as to where the problems are and whether, as you said, they are something you can live with.

Pazdur: We’re formulating an idea on it. I don’t want to give the impression that we’ve made a decision on an NDA or BLA before it has been submitted. One of the points I emphasize to the review staff is to keep an open mind. I tell them, “ You will hear arguments from the sponsor regarding a particular viewpoint, but keep an open mind regarding whether that argument is cogent, or if it is just smoke and mirrors.”

Although we’re starting a discussion, by no means have we formulated an approval decision. But we are already thinking about the major issues.

And for applications that are not going to an Oncology Drug Advisory Committee meeting, I’ve advised the review staff to start selecting special government employees, members of ODAC or other disease experts to start having conversations regarding the application.

We can’t have multiple people on the same time on a phone call, because that would constitute an advisory committee and would be inconsistent with the regulations. But one can make a phone call with a properly screened special government employee to discuss an application. And we have frequently included patient representatives on these calls or a separate call.

What is an Oncology “Breakthrough”?

Q: It sounds like what you’re describing is really the opposite of that “black-box” impression that many stakeholders have – that an application goes into FDA and then you don’t hear anything for a period of months. And it also sounds like what you’re describing is kind of a Breakthrough designation. You’re encouraging this “all hands on deck” attitude towards these oncology applications. So I wonder: What’s different for a Breakthrough designation in your office, versus a non-Breakthrough?

Pazdur: One of the things that we have with Breakthrough designation are other people’s opinions regarding the application, and that would include Dr. Janet Woodcock, Dr. Bob Temple, Dr. John Jenkins, the safety people, etc. So a Breakthrough application has a much broader exposure at FDA than one undergoing a traditional review.

Nevertheless, many of the principles of Breakthrough therapy we had been doing in oncology for many years. For example, when we have internal discussions with 50 medical oncologists in a room and we’re presenting, for example, the first flush of the NDA or BLA, there will be a variety of opinions shared.

And believe me, there are not very many shy people that are sitting in that room, and sometimes there are heated discussions: “This is wrong.” “This is right.” “I could live with this.” “You’re being too picky.” “Let’s look at other applications that we’ve done that have demonstrated the same type of problem.” So, it’s really a discussion of where we want to go, and can we bring other things to the application.

One of the major principles of the Breakthrough therapies is that we do not want to expose patients unnecessarily to relatively ineffective therapies. So when one is comparing their drug in a randomized study to a relatively ineffective therapy, how can we really look at the statistical plan? How could we try to wrap this up as quickly as possible, to get the requisite information that we would need for approval of the drug, while at the same time sparing patients unnecessarily to a relatively marginal therapy?

Is the “Program” Slowing Down Expedited Reviews?

Q: The Office of New Drugs is operating under the new review “Program,” which allows FDA a slightly longer review time in exchange for additional agency-sponsor communication. I have to wonder whether the constraints around the Program are slowing down the review of products under expedited pathways, such as Breakthrough or Accelerated Approval. For those applications, is the timeframe so shortened that the Program is getting in the way of an efficient review?

Pazdur: That’s a question that I’ve asked myself, and I think the answer to that question is basically unknown at this time. I want to be very careful in what I say about this.

If I tell the review staff that they have 10 months to review an application, and previously they had eight months, guess what will happen? Think back in your college days when the professor said, “Your term paper is due May 31st. I would appreciate it if you could get the term paper to me as early as possible.” Well, let’s guess what 99% of the students are doing on May 30th: they’re sitting at their word processors – in my days, their typewriters – typing away. It’s almost human nature.

The purpose of the Program under PDUFA V was to get the review time done at the specified period – six months for a priority review – and then have this two-month period of additional time. The reality of the situation is that many people work toward a deadline, and even though we would like to have the reviews done early, there are just certain things that come up.

It’s really a work in progress. I know the press is constantly comparing timelines of reviews; that’s only natural to do. But one has to understand that each of these applications is very unique. There is no such thing as a cookie-cutter application. There are problems with clinical site inspections. There may be problems with manufacturing that delay the approval of the drug. There may be pharm-tox issues. There may be dosing issues. There may be toxicity issues that need to be addressed.

So I really don’t know how to answer that. But I think it does deserve some scrutiny. And I think on the part of industry, they have to ask themselves are they getting what they want out of these two additional months as they go into perhaps another round of PDUFA negotiations, or if they’re having adequate discussions with the division?

For many of these applications that we get, we know we’re going to approve the drug. The sponsors know the drug is going to get approved. The drug has met its primary endpoint. It has a big effect, especially with some of these Breakthrough therapies. The question isn’t, “will the drug be approved?” The question is, “how fast we can get the drug approved?”

The critics say: All you’re really doing is improving the approval time by two months or three months. And really, when one takes a look at the total picture of drug development, that two-month period of time is really a small fraction of the years that it took to develop a drug.

I caution people about that, because time is not equal in drug development. When patients know the result of a Phase III study, and they are facing a terminal disease, that drug becomes extremely important to them. They don’t know that when the drug is going through Phase I or Phase II drug development. Not all time is the same in drug development.

Getting these drugs out to patients as early as possible is a priority of the oncologists in our divisions and my own personal priority.

Now, you could say, well, you could have expanded access programs that could meet this need, and that’s true. However, let’s face it: Expanded access programs – and I’m from Chicago – might occur in Evanston and in Wilmette, and in the wealthy and very educated suburbs. They probably don’t occur in Cook County hospitals and the inner city hospitals to the same degree as we would like it to be. So there is some inequality in an expanded access program.

Collaborating with the Diagnostics Center

Q: I also wanted to ask you about your relationship and collaboration with the Center for Diagnostics & Radiological Health. Targeted oncologics and companion diagnostics are becoming more important as industry focuses personalized medicine and subsets big diseases. Industry would probably say that the drug center is a bit open-minded and creative than CDRH when it comes to regulatory policy. How do you work with CDRH? Are there ways to improve that relationship?

Pazdur: I know this might sound trite, but geographic proximity and having people on the same campus is really important, and the CDRH folks are now in the adjacent building. They are attending all our meetings. They are fairly integrated into the process. So I would say that we have excellent communication with them on the development of these in vitro diagnostics.

And we are all acutely aware of the time constraints of oncology drug approval and the need to get these drugs out. The guidance clearly stipulates that for life-threatening diseases, if the agency felt a need to get the drug out there and it didn’t have an approved companion diagnostic that we could go ahead and approve a drug without one. Nevertheless, I think CDRH has demonstrated a really high degree of flexibility and need to work with us, and a willingness to meet expedited review guidelines.

But there are only a certain amount of things that we can push through in a quicker-than-expected fashion. I make this point to the staff from the day one: “I want you guys to do a good job, the best job that you can, on the review of this application. I do not want somebody to come back to me at the end of the review cycle and say, ‘Dr. Pazdur made me approve this drug,’ or ‘Dr. Pazdur tried to push this through the system and I wasn’t ready to approve this drug.’ I don’t want to hear this.”

So when we’re making these timelines internally in our divisions, the basic principle is: do you feel comfortable, from your review perspective, in approving the drug at this time? Will you have adequate time to look at this? It is not a ram-rod. I think it is important for people to realize that the quality needs to be there for these reviewers.

Now, that doesn’t mean that we can’t – and this is one of the principles of Breakthrough therapies – think of doing things smarter and quicker. For example, having two reviewers work on an application rather than one reviewer; one doing safety, one doing efficacy, and having a greater collaboration with our statistical colleagues. Those are things that could expedite the review of an application; discussing problems earlier-on rather than having them fester.

I have a very open-door policy. I want to hear if there is a problem as early as possible, so I could step in, either to say, “hey, all, this is not a really serious problem. You’re making too much out of it.” Or, “is it really a problem that we really need to address this with the sponsor? And let’s get them on the phone today to start discussing this.”

Q: An important part of the review can be an advisory committee meeting. You’ve said before that the Oncology Drugs Advisory Committee is typically reserved only for real “problem” applications. But I can think of an example, and I’m thinking of Perjeta, where it seemed like FDA was on board with an approval, but it wanted to use the advisory committee to inform other sponsors about drug development, in this case, in early-stage breast cancer.

Pazdur: Generally, we take an application to an advisory committee, granted, if there is a problem – or if we want to shed light of day on an especially new endpoint that we’re using. With thePerjeta application, both the review staff and the sponsor, Genentech, were on the same page regarding the major points of this application.

I will not say that the entire breast cancer community was on the same page regarding this, because we heard pros and cons from the breast cancer community regarding this application. So we did want to have a public discussion where we could hear both sides of the argument, if people wanted to come forward, at the open public hearing or from our advisory committee.

We were dealing with a unique endpoint. There are obviously problems with that endpoint that have not been worked out. However, we believe that the totality of evidence with that application, considering a very large, clinically meaningful improvement in overall survival, a completed adjuvant trial already, really kind of pushed this into a special category.

Pazdur’s Reversal on Single-Arm Studies

Q: I have to ask you about single-arm studies. You recently made some pretty bold statements where you said that we should think about a return to single-arm studies. And then at the same time, we have the Inclusig market suspension after being approved based on a single-arm study. Does that suspension give you any pause at all in accepting single-arm studies, or was that just sort of a one-off issue? What are the limitations there, and how can FDA ensure safety?

Pazdur: There are problems with single-arm studies. Single-arm trials really don’t give you an idea of safety of the drug. It doesn’t have a comparator to it, so basically, all adverse events should be attributed to the drug, in a sense. You can’t really tell what is going on from an adverse event profile. You can’t take a look at certain time-to-event end points, or any time-to-event end points, such as overall survival and time to progression. There are limitations to a single-arm trial.

I was not a big fan of single-arm trials several years ago. So what changed? I didn’t change, let me tell you that. The drugs changed. The drugs got better. There’s a big difference between a drug with a 15% partial response rate and a drug that has a 50% or 60% partial response rate, especially when one is dealing with a drug or a disease situation that has no effective therapies.

So what has changed is basically the effectiveness of the drugs. Most of the problems with oncology applications, unlike other therapeutic areas, center around three things: efficacy, efficacy, efficacy. However, we really have to start rethinking some of that, as we get into more chronic use of medications. And that brings us to the point of randomized trials looking at safety.

When one has a disease situation where there really is marginal available therapy or no therapy at all, and there’s very high efficacy in the study drug, one has to ask, is a randomized trial ethically feasible even to do? Maybe we need to answer the safety questions either in another disease setting with the drug – for example, in a les refractory disease population – or through registries or some other method.

In regard to safety, we have to start taking a greater look at safety in oncology drug applications, especially when we have more effective drugs. In the era of cytotoxic therapies that I grew up in, in the 1970s and the 1980s, there was this mantra: more is better. As we get to chronic oral dosing of medications, we have to start taking a look at how many patients are having significant dose reductions.

What is a tolerable dose? Can patients tolerate chronic grade 1 or 2 toxicities for weeks at an end, rather than just taking a look at grade 3 and 4 toxicities? And we have to be realistic when we describe grade 1 or 2 toxicities – and I’ve seen this on several applications, which bother me – what is a grade 1 myocardial infarction? What is a grade 1 stroke?

When we talk usually about grade 1 or grade 2 toxicities, we’re usually talking about grade 1 diarrhea and grade 1 mucositis, and grade 1 headache or something like this. But if you’re inflicting end-organ damage on the heart, or on the brain, I don’t care if somebody reversed it. We’ve got to be aware of this, and this is probably a spectrum of toxicities that we’re seeing, that we have to cull out from that application.

The other major issue with these single-arm trials is, we’ve got to get rid of this investigator-assessed ascertainment. Nobody knows what caused a myocardial infarction, whether it was the drug or whether it was the underlying disease process, or the patient had preexisting heart disease. We can’t tell in a single-arm blinded trial.

http://www.elsevierbi.com/publications/rpm-report/10/2/cancer-therapies-the-breakthrough-era