Director of the FDA’s Oncology Center of Excellence Discusses Expanded Access, Accelerated Drug Approvals

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Dr. Clifford A. Hudis (CH): Welcome to this ASCO in Action podcast. This is ASCO's monthly podcast, series where we explore policy and practice issues that can impact oncologists, the entire cancer care delivery team, and the individuals we care for, people with cancer.  My name is Clifford Hudis, and I'm the CEO of ASCO, as well as the host of the ASCO in Action podcast series. For today's podcast, I am delighted to have as my guest, Dr. Richard Pazdur, the Director of the Food and Drug Administration's Oncology Center of Excellence.

The OCE was established to expedite the review of novel cancer therapies and products by bringing together expertise from across the FDA. And we'll touch on this a little bit during our conversation. Dr. Pazdur, welcome and thank you for joining me today.

Dr. Richard Pazdur (RP): It's a pleasure Dr. Hudis.

CH: Thanks. So I want to kick off our discussion by diving right into a hot button issue, expanded access. Can you provide our listeners with some background on this, and explain what the FDA's expanded access program is, and why an oncologist might want to pursue expanded access for an individual patient?

RP: Of course. The FDA's expanded access program provides a way that patients with serious or life-threatening diseases or conditions such as cancer can try investigational medical products for treatment when no satisfactory therapies are available, and when there is no opportunity for the patient to enroll in a clinical trial. The process-- to make a request, the patient's physicians will approach the pharmaceutical company to ask for its agreement that the company will provide the medical product.

The company has the right to approve or disapprove the physician's request. Then the physician needs to send the request to the FDA. This process can be complex to navigate, particularly for oncologists or physicians who don't have experience working with the clinical trials or these types of requests.

FDA allows the vast majority of these requests to proceed. And the FDA has been working to improve the expanded access programs for a number of years, including the development of a more streamlined application process, a more streamlined form. But for many key health care professionals, especially those not familiar with the expanded access program, this process may appear confusing or somewhat burdensome.

CH: And so is this a segue to Project Facilitate, which you announced at our annual meeting a few weeks ago? Can you talk a little bit about that and, its practical implications?

RP: Yes. The Project Facilitate call center is a pilot program only for oncology that will serve a single point of contact. We have FDA oncology staff there, oncology nurses, oncology pharmacists who will assist the physician and their health care team throughout the process to submit and expanded access request for an individual cancer patient.

This is a concierge service to support the patient's medical team throughout the process. It ranges from the initiation of the FDA form 3926. The process will also provide information about IRBs, particularly central IRBs, and really will also follow up on the status of a given patient to determine if that patient has received any benefit from the therapy and if there were any adverse events that need to be reported to the FDA.

CH: So imagine that Project Facilitate works as hoped for. What's the thumbnail before and after experience? That is, how will things appear to be different to the physicians and to the patients?

RP: It should make the process easier for physicians to get information that they need to submit an expanded access request. As I said before, it's often somewhat complicated, especially for physicians don't have experience with either the drug or with the process. And it's obviously easier to talk to somebody over the phone to ask specific questions rather than just being directed to a website.

We're also working in conjunction with Reagan-Udall Foundation for the FDA, which started the expanded access navigator website to educate patients and health care professionals about the expanded access process. This navigator approach offers information provided by companies about their expanded access policy, and now includes the expanded access programs listed in ClinicalTrials.gov.

Patients and physicians can look for treatment options. They could discuss clinical trials, and company information could be provided at the navigator at Navigator.Reagan-Udall.org. So this is really to give patients and their physicians information about what is out there.

Once the patient obviously has this information and their doctor, then the doctor can utilize the Project Facilitate, which allows easier access to actually submitting these forms and going through the actual process. I'd like to emphasize that companies are now required by the 21st Century Cures Act to publicly list their expanded access policy. And the Reagan-Udall Navigator website helps them comply with that requirement.

Again, so once the physician and the patient have identified the investigational therapy they want to try, the physician or other members of the health care team then can contact Project Facillitate for assistance in locating IRB resources and help with the FDA form 3926.

CH: So I think you mentioned this when you launched this or announced it at the annual meeting just now, that physicians do already-- or at least before project facilitate often would successfully go straight to pharmaceutical companies and ask for treatments. And I guess in some cases they'd be denied, and in some cases they would be approved. And that would be through the company's expanded access programs.

Obviously, that means that regulators wouldn't necessarily know the full extent of expanded access use. So assuming that Project Facilitate will allow the FDA to collect much more data on expanded use, how will the data be useful? And obviously, I'm hinting at the fact that some fear that it will be actually a negative.

RP: Well, prior to launching Project Facilitate, the expanded access requests for cancer patients arrived at multiple places within the FDA and were forwarded separately to FDA oncology or hematology

 

divisions. Sometimes these requests could be delayed, being sent from one place to another in the agency. So this gives a focus point for physicians to contact.

In addition, we're seeing that most of the expanded access requests were coming from patients and physicians at larger academic centers. The patients who don't live near these cancer centers and may not be able to get on clinical trials can also hopefully have access to investigational agents by having a more facile and easier process to use here.

We're also seeing that many companies have turned down requests from patients, and we have no idea what really the number of requests a company may get if they're turning down these requests. Because generally, they don't come to the FDA. So really, by having the initial contact at the FDA we'll be able to determine number one, the number of patients that are requesting a single patient access.

We'll also be able to determine and discuss with the companies their reasons for denying these requests. And there could be multiple reasons. And we also have a process in place that can follow up with what are the benefits that an individual patient may have from this therapy or, as I stated before, were there any adverse events.

We have also heard this kind of urban myth-- and I label that in quotations, "urban myth," that companies fear that perhaps adverse events may be held against them when their drug is coming for drug approval. We have not done that. We take into context where the adverse event reporting is coming from. And there really are no instances that I am aware of in oncology where a report of an adverse event has delayed or curtailed an approval of a drug.

CH: So really, this is a bright ray of sunshine on a dark corner of drug access. And if it works right, you'll just have much more understanding of the overall use of expanded access. Right?

RP: Yeah. I think that gives some clarity to the process here. Here again, we don't know the numbers at this time of actually the number of patients. We only know the numbers of patients that receive a affirmative position from the drug company regarding that the process can continue.

But we don't know the numbers of patients that may be requesting single patient access and are denied by an individual drug company. And also, the reasons. And, as I stated before, there can be very legitimate reasons, including inadequate supply of the drug, lack of support staff to follow up on these drug requests, potential interference with clinical trials that the patient may be eligible for.

CH: You just used a phrase about patients requesting. And I thought as you described this process you were referring to physicians requesting on behalf of patients. And so I do want to ask, are there resources that are aimed directly at patients or is it really solely aimed at the oncologists in this case?

RP: Well, here again, this is a two-prong process. Project Facilitate, the FDA portion of this, is for physicians to call up for assistance in filling out the form and also navigating the process once the decision is made. The other prong of this is, as I stated before, by Reagan-Udall foundation, which patients can call to look at what our options available to them that are potentially listed on ClinicalTrials.gov. And that is also for patients and physicians. However, the portion of the program that is Project Facilitate is for the requesting physician.

CH: All right. Well, that's clear. So once we talk about patient's involvement, and even many physicians I think for that matter, we quickly can drift towards the very heated discussion that took place in public over the last year in the area or that we call Right to Try. And I wonder if you could talk for a minute and help us, for the listeners, make this distinction between expanded access and Right to Try.

RP: Of course. These programs, Right to Try and single patient INDs are really mutually exclusive programs. The main difference between these programs are first, that under Right to Try the drugs have to complete a Phase I trial. For single patient INDs, it could be done anywhere, even within the context that the drug is being conducted in a Phase I trial.

However, the major difference is that the FDA and the IRB does not review Right to Try applications, whereas under a single patient IND, the FDA obviously has to give permission for the patient to proceed as well as an IRB has to review these requests.

CH: So to be very clear, Project Facilitate is supporting the single patient INDs, and Right to Try is a separate matter entirely.

They are distinctly different programs. Project Facilitate does not apply to Right to Try. That is an independent, separate program.

CH: Great. So, you know, one of the problems for a busy clinician is figuring out how to do all this under pressure with a sick patient, and the other pressures of clinic and administration and research. If our listeners want to learn about this more casually, where can they go not under duress, just to start reading up and learning about how to access the program?

RP: They could go-- physicians can go and learn more about the program at our website, www.FDA.gov/oce. The Project Facilitate phone number is 240-402-0004. That's 240-402-0004. And the email address is [email protected].

CH: That's great. So hopefully, some of our listeners will take advantage of that and learn about this when they're not under pressure so that they're familiar with it if they have to turn to it some months later. Now you mentioned that the host is the Oncology Center of Excellence. And I mentioned in my introduction that we would want to talk a little bit about that.

CH: You've been at the helm of the OCE since it was established a little over two years ago, I think. Now that you've been in the role a while, I wonder if you could talk a little bit about your view of what the OCE should be accomplishing, and maybe how that aim has evolved over these two years.

RP: Yes. The OCE basically was an offshoot of the Moonshot Program several years ago, and was aimed to be the first center that coordinates activity among the therapeutic center. Obviously, at the FDA there is a center for drugs, a center for biologics, and a center for radiologic health and devices.

And they all can review oncology products. The OCE has a designation to really coordinate the activities, particularly in the clinical review of the products that involve the treatment of cancer. So, this is a unique center within the FDA, and is somewhat of an experiment at the FDA to see how we can really coordinate the activities of drugs that affect cancer patients.

And here again, the oncology center is primarily designated for the clinical review. And we don't really get into the manufacturing of drugs. That's handled in the individual centers, whether it be a biologic and CBER, the Center for Biological Evaluation and Research or CDER, the Center for Drug Evaluation and Research.

With that given said, in addition to the actual bread and butter of reviewing applications, we have many research projects that we're doing. We have a big project looking at real world data. We have a project looking at updating labels called Project Renewal.

We have, as I stated before, this project that we launched at this year's ASCO, Project Facilitate. We also have a project aimed at really improving our relationships with international drug regulators. We have monthly meetings, teleconferences with five different regulatory agencies throughout the world to go over applications and discuss different regulatory policies.

We have a host of a symposium that we conduct both here at the FDA, inviting external stakeholders including physicians, leading academics, patients to come to the FDA really to discuss important topics to our drug reviewers and the entire discipline of regulatory and oncology, so to speak, how we make decisions in medicine.

We have a whole, also, program that we're developing aimed at educating physicians and other health care professionals for educating other health care professionals on how we evaluate drugs, what our thought processes are here at the FDA. So, in addition to the regulatory work, there is a whole body of scientific work that we're also doing, including independent research on different databases, looking at patient populations more likely to respond to different drugs, ways of evaluating and describing toxicities, ways of really looking at patient experiences while they're getting drugs, and different ways of reporting patient reported outcomes.

We'd like to thank ASCO, obviously, for their assistance during and helping us with many of these projects throughout the year, especially the educational projects involving fellows, involving different topics that we've found of interest that needed to really have a public disclosure in the community, really, to get input from leading academics, as well as treating physicians.

CH: Wow. You are busy. And there's a lot we could unpack there. But I do want to pick up on a couple of things. First of all, you described this as an experiment, so I'm curious. And not to put you on the spot, but if you have an experiment, I presume that just some metric that you would use to call it a success or failure. And I wonder where you think you are right now in that regard.

It sounds like you've gotten a tremendous amount done. But are you satisfied, for example? Have you covered the ground you wanted to or do you think that you could be doing more?

RP: Well, people who know me realize that I'm never satisfied. So, I think we're in the middle of this experiment. I think it's going quite well. And I think that this is really going to be aimed at-- and the evaluation of the success or failure of this is going to be really how the individuals that work here at the FDA really evaluate drugs and how we facilitate the evaluation of drugs.

And also the really important of retention of staff here at the FDA is a major issue, also. And I think many of the projects that we have ongoing really develop our reviewers in really having a real world approach to how oncology drugs are used. So it's very difficult to say what success and failure will ultimately be. But I think we're on, really, the correct path, and pretty much a straight path of looking at a successful venture here.

CH: You know, one of the things you said reminded me of another urban myth. And I don't know if you realize this. But when you describe the careful coordination with, I think you said five regulatory agencies around the world, it raises the myth, I believe, but you can address this with some facts, that many people in the United States believe that others around the world have faster access to a broader range of effective therapies. I wonder if you want to expand on that or comment on that at all before we move on.

RP: Well, that is an urban myth, and probably was generated 20, 30, 40 years ago when that may have been the fact. Obviously, that antedated my coming to the FDA. But I can say the vast majority of drugs are approved first in the United States.

And those include very important drugs such as the PD1 drugs, the targeted drugs, et cetera. They are approved first in the United States. We have taken a very active approach to really rapid approvals of our drugs without sacrificing quality, by having a smarter approach to how we review these drugs, with putting multiple reviewers on particular applications, by cutting down on unnecessary paperwork that many of our reviewers had to do, and really focusing on really the core material that we have at hand, and really emphasizing does this drug really demonstrate safety and efficacy.

At the end of the day, I charge all of our reviewers with the following statement. Would the American public be better with this drug than without it? And that's the ultimate decision that we have to make at the time of approval.

CH: Well, that's another perfect segue to a hot topic, which you and I have discussed actually offline before this. But I'm going to come back to it. The expedited approval of anticancer therapies was recently the subject of a paper in The Journal of the American Medical Association.

And if I remember correctly, they looked at 93 cancer drugs that had been approved through accelerated approval process. But what they claimed is that only 19 of the 93 clearly extended the lives of the patients taking them. That's a value judgment, obviously, about why drugs are approved and introduced to the market. But I wonder if you would want to talk a little bit about your view of some of the complexities and challenges that are inherent in accelerated drug approval, and what your view is of this particular study of the approval outcomes.

RP: I think many times people don't understand that it isn't just about overall survival. Obviously, that's the gold standard. But we've had very careful discussions throughout the years that there are many ways to evaluate benefit to the patient.

And that includes reduction of the size of the tumor, delay in the progression of the disease, the establishment of complete response rates in hematological diseases. So we have to have some flexibility, both in terms of how we approve drugs and what clinical trials we're going to ask for after drugs have been approved on the accelerated approval pathway.

Although overall survival is a very important end point, it's an important efficacy endpoint as well as a safety endpoint, it does have limitations. As we move more toward a targeted therapy and subsegment common diseases into molecular subtypes, many times we find that we have very limited populations.

And simply, we don't have the size of a population that we approve the drug on to really do a large, randomized trial.

So we have to weigh that issue with what type of trial we're going to ask for, both with the initial approval of the drug as well as with, perhaps, the subsequent studies that we ask for after an accelerated approval. In addition to that, many times we find that we have situations where the disease itself may have a very long natural history, such as CLL or other diseases that may have very long natural histories, where one cannot really do a long-term survival study because it would extend many, many, many years.

And many times-- and I think we have to be realistic about this, that there may not be equipoise here to allow a randomized trial to be done looking at overall survival as a primary end point. For example, if we already have information that a drug may have a response rate of 50% or 60% and the comparator drug may have a response rate of 10%, patients will not want to go on a study that looks at overall survival as the primary end point.

And many times, we have to take a look at time to progression or progression free survival and those end points, and actually allow for a switch in therapies or crossover at the time of disease progression, which renders the evaluation of overall survival somewhat difficult, and may confound that evaluation.

So, there are many reasons why overall survival, although a gold standard, may not be applicable to all situations. And I think that's going to be increasingly so as we get into a more targeted therapy approach and have better definitions of who is going to respond. So here again, it's long natural history of diseases either by its natural history or by the therapies that have been approved that prolong disease.

It could be due to the limited populations, which preclude a randomized trial. And it could be due to the lack of equipoise, which really bands that patients have access during the course of disease. I think a much more important question, and one that we are constantly looking at, is not so much what does an individual drug do to the natural history of the disease and prolonging survival in patients that have metastatic disease, but what is the impact over the years of multiple drugs being approved on the basis of progression-free survival or response rates when they are used either in combination or sequentially.

And we could see that, for example, in multiple myeloma, where the course of that disease has been significantly changed, and patients' lives have been prolonged. And the vast majority of the drugs that have been approved have been on non-survival endpoints. And this is true not only for multiple myeloma, but also probably for renal cell cancer.

CH: Yeah. That's interesting. It's a challenging analysis, of course. But that would be a very interesting, essentially public health roll up of all of these incremental decisions. Right?

RP: Correct.

CH: Yeah. So, as I said before, the OCE has been in operation just over two years. During that time, more than 80 therapies and products have been approved, I think. Right? And there've been more than a dozen guidance documents approved, 60 workshops and symposia for oncologists and for patients.

And there were several of those workshops that we at ASCO were privileged to co-sponsor along with you. This is the favorite child question. But what's your proudest achievement so far?

RP: A difficult question, but an easy question, too. It's about the people that work here and the patients that we serve. And I think my brightest moments are when we see the development of our people coming in and taking leadership positions both within the agency in a regulatory context of their job, but also in the academic fields and participating in conferences, publishing papers, and really finding enjoyment in the job that they have outside of the day-to-day regulatory activity.

One of the things that I have always emphasized since I came here 20 years ago from an academic medicine position at M.D. Anderson is really to give the agency a much more academic perspective. And I've always stated that I think we do much more academic work here at the FDA than many academic centers. And I'm not talking about the generation simply of papers or research grants.

I'm talking about actually critical thinking of what goes on at an application, since we have a multi-disciplinary team of statisticians, clinicians, clinical pharmacologists, toxicologists, manufacturing people that all work together. So it's really about-- my greatest accomplishment is really about the young people that have come in that I've mentored, and really have assumed roles, and really will be my lasting legacy here.

But I also want to emphasize that one of the things that I have repeatedly highlighted to this staff is really to consider the patient in really any regulatory decision. Here again, it's not about a P value. It's not about a primary end point. Granted, those things are important, but we really have to bring together the whole body of information about a drug in making a regulatory decision and making that a patient-focused thing. And as I stated before, at the end of the day will the American patient-- will the American public be better off with this drug than without it?

CH: Well, Rick, I got to say that's an inspiring description. It makes me wish I were younger, and maybe I could come and be mentored. But alas, it may be too late for me. But we really are proud to work with you, and to work with so many of your staff in many productive collaborations.

I want to thank you again for joining me today for this ASCO in Action podcast. We always appreciate your expertise and your perspectives. And we look forward to continuing to work with you to ensure that patients with cancer have access to safe and effective treatments.

RP: And thank you, Cliff. It's been a pleasure. And here again, I really think ASCO for providing a lot of resources to us in conducting symposium, and really in fostering better cancer care for patients. I think that's the ultimate goal of both organizations.

CH: It sure is. And I want to remind our listeners that you can follow the FDA Oncology Center of Excellence on Twitter. Their handle is @FDAOncology. That's one word. You can follow me @CliffordHudis, and you can follow ASCO @ASCO. For more information on the latest cancer policy news and updates, visit ASCOAction.ASCO.org. And Rick, I'm going to ask you once more to remind the listeners of the way they can access Project Facilitate.

RP: They can learn about Project Facilitate from our website at www.FDA.gov/OCE. And our project facilitate phone number is 240-402-0004. And the email address is ONCProjectFacili [email protected]. ONCProjectFacilitate is spelled O N C P R O J E C T F A C I L I T A T E @FDA.HHS.gov.

CH: That's great. So until next time, I want to thank everyone for listening to this ASCO in Action podcast.