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FDA's Patient-Focused Drug Development Guidance

July 22, 2019



Good morning everyone. Thank you, Bill, CRF Health, for inviting me to speak today. As I was introduced, my name is Nikunj Patel, I work for AstraZeneca. I’ve been there for about eight months, seems like it was just last month but time flies. And I’ve been working on—I develop PRO strategy for our oncology area, within oncology TA in collecting patient perspective throughout a clinical trial. Thank you, TJ, I think the story you shared was incredible. I mean I learn so much every time I listen to patients, I learn something new. So thank you for sharing. I think you really staged it for me to take it from here into how do we actually incorporate patient voice. And I think we want to learn more from patients like you and other partners, how do we do a better job at it.

This is my disclaimer. These are my own views, they don’t necessarily represent the position or policy of AstraZeneca.

In this presentation, there are three things I’d like to talk about. One, a brief PFDD background—patient-focused development background—a general overview of the guidance series that the FDA is starting to gather, and industry perspective on those.

Quick question for you all, just to make sure you guys are all up. How many of you actually know what patient-focused drug development is? Have you heard of it? Okay, wow, I think that’s a lot of people, Bill. I should just stop here probably. What do you think?

According to the FDA, and you can find this on the website, PFDD “is a systematic approach to help capture and ensure that patients’ experiences, perspectives, needs, and priorities are captured and meaningfully incorporated into drug development evaluation.” And further on, “patients are uniquely positioned to inform the understanding of the therapeutic context for drug development evaluation.” I think TJ alluded to that earlier. I want to emphasize, the premise behind the entire PFDD initiative is really, patients are truly expert in their own disease. And that’s something that Dr. Woodcock had said, and she’s a senior director at FDA and throughout many of her presentations publicly, patients are uniquely positioned to really help us understand the disease.

The PFDD initiative started in 2012 with the FDASIA which is FDA’s Safety Innovation Act, also known as PDUFA which is Prescription Drug User Fee Act, where the agency committed to conduct 20 disease area public meetings, such as neuropathic pain. I had an opportunity to represent FDA when I was at the agency at the time, lung cancer, Parkinson’s disease, and I believe the agency has conducted 24 such meetings. And now actually encouraging external patient groups and other advocacy organizations to actually conduct externally led PFDD meetings because they’ve been really successful in identifying public health needs and really listening to patient voice. Bill alluded earlier in his presentation about PRO guidance too, and I think that’s really an influential document for the broader PFDD initiative that really outlines the agency’s views on patient-reported outcome measures used in medical product development.

What is PFDD guidance series? It’s one central—maybe the central—strategy to meet the primary goal of PFDD to enable incorporation of patient voice systematically with scientific rigor throughout the drug development. The 21st Century Cures Act, many of you may have heard of that, it was passed in 2016 and recently FDA Reauthorization Act of 2017 which is the PDUFA VI, they also mandated that FDA devolve these guidance documents to help stakeholders, not just pharmaceutical industry but also patient advocacy organizations, patient groups, other stakeholders, to understand what PFDD is and how they can integrate a patient focused drug development in what they do.  So in order to do that, they committed to do four method-focused guidance documents on how to collect and submit patient experience data and other relevant information from patients and caregivers for medical product development and regulatory decision making. I know TJ sort of alluded to earlier about Dr. Gottlieb from FDA, about the importance of collecting data and submitting the data to agency when the benefit risk decisions are being made. So these guidances provide really good overview and in-depth guidance on how you do that actually methodically.


As I mentioned, these guidances are targeted for a broader audience. I’m not sure if you have any opportunity to take a look at the guidances. Although they may be a little too technical, they also are trying to make it less technical so the average person, a patient advocacy organization, who don’t have the knowhow, they don’t have the scientific expertise, they can still read the documents and understand and try to integrate it in what they do.

As I mentioned, FDA to publish four method-focused guidance documents sequentially. The first one actually came out earlier this year, the draft version. The guidance is Collecting Comprehensive and Representative Patient Input. This guidance really focuses on what should be the sampling strategy, what should be the sampling methods that one can consider when you are planning to collect representative patient input to understand the disease burden, to understand the treatment. For example, let’s say you are interested in developing a lung cancer patient-reported outcome measure. What kind of patient are you going to talk to? What should be the clinical criteria for those patients? What should the demographic? We want to make sure the information being collected from patients is representative of those patients. So it’s really important to integrate the scientific rigor from the get-go.

It also touches on things like how to develop a research question. Most of you in the industry probably know that, but again, going back to the broader stakeholders, people in patient organization, they are great advocates, they may not have the full scientific background, so this really helps in guide them in how do we do this. I have to say, these guidances also really help with training people in the industry too. They’re really nicely well written and provide really good content.

Guidance number two and three, well they have not been released, but there were discussion documents related to those guidances published earlier this summer. Has anyone had an opportunity to attend the meetings that occurred in October, by show of hands? I see a few people attended the October meeting. That really described some of the content in guidances two and three.

Guidance two, it talks about Methods to Identify What is Important to Patients. One of the key methods I would say that’s really covered well in that is a constant elicitation, as we call it in the PRO research, where you’re trying to identify what’s important from the patient perspective if you are develop a PRO measurement, your caregiver as well, what are the things they care about? Is it survival? Is it a symptom they’re having? Is there a part of their life that is really important to them? I’m going back to TJ’s example, to him it was really important to be a husband, be there for his children. So those are things that we try to identify, what is meaningful to patients. If you are developing a lung cancer measure, for example, what are the symptoms that patients have with lung cancer? Cough, dyspnea, chest pain. Or what are the impacts? Is the condition physically debilitating, are they able to participate in physical activities, are they able to participate in their hobbies, things they care about. Are they able to drop their child off at school or pick their child up from daycare. So really identify what are the things that the patients find most meaningful to measure, to help understand the quality of life in that sense.


The third guidance, which is really about, I call it mother guidance, and you may have heard the terminology, or mega guidance, because it’s really discussing COA evidentiary considerations for all four types of COAs. I know we commonly talk about patient-reported outcomes, patient outcomes. These are a direct measure of patient perspective. There are also clinical-reported outcome measures as well, where a clinical, for example if you have Parkinson’s disease, clinicians are often assessing patients’ body movement. So that’s another example. Performance outcomes, six-minute walk test you may have heard of, commonly used in heart failure studies to understand patients’ physical stamina, their walking capacity. Observer-reported outcome, especially in pediatric drug development where a child cannot express, they can certainly express they’re having pain, but they may not know what’s my pain level from 0-10, they may not have that cognitive insight to really give you an accurate count or assessment of the pain. So we rely on observer-reported, parent-reported outcome measures. So this guidance really touches all four different types of COAs. And if you were at the meeting in October, you may have heard from FDA that PRO guidance will be replaced, and this is the guidance that will replace it. There will be, as mentioned in the meeting, attachments that will discuss specific considerations, unique characteristics of each COA type that will be added to this guidance in the future.

This is probably the most technical guidance, I would say, out of others. And the reason is, it’s probably really difficult, I would say if you’re a PRO expert, to really make it in a non-technical— So I think the FDA tried really hard, I would say, but it’s still quite technical. But you know, it’s an important document and it’s something that I know I will be reviewing very carefully, all of these of course, but that one is particularly because it really talks about methods, how do identify and I support oncology, lung oncology specifically, this is what I’m doing on my day-to-day job. What PRO measure do we want to use for these patients? What is important to patients? Do I need to develop a new measure which may take longer time, do I have time for that? And can we use a measure that’s already existing, can we modify it? So again, this is an important document, all these are.

And the fourth guidance that the title has not been announced yet, it’s really going to talk about topics related to COA endpoint development. So here, we identify from patients, they find the symptom thing really important. Here’s how we’re going to measure those symptoms using this tool. Well how do you actually develop an endpoint? An endpoint and a COA measure are two different things. COA measure collects certain characteristics of the symptoms, but endpoint is you are actually able to define what is an improvement, what is a time for determination. So that’s how things are a little different. And this will actually go into talking about more of a developing and an interpretation, how do you interpret the data that you’re going to get, is a 20-point change meaningful to patients, what does that even mean. What is it equal to—does that mean I’m able to go and pick up my kids from school, or does that mean I’m able to go to bathroom. So it’s really I think it’s going to be an important guidance. It will also talk about instrument administration and implementation. I think, talking about eCOAs, I think it’s going to talk about quite a bit of that, from what I heard at that meeting in October, and what would be a meaningful patient change that I alluded to. And possibly other topics.

From my perspective, I think it’s been quite supportive. FDA’s efforts to incorporate patient voice in drug development and regulatory decision making I think is fantastic. And it’s quite welcomed. Hearing from not just within AstraZeneca but also many other companies that we interact with in the outside, in a competitive arena.

PFDD guidance series provides FDA’s current thinking. Since the PRO guidance, at least informed—you’ve probably heard FDA presentation at public meetings and various conferences, the DIA for example, that some of you may have attended, this is probably the most current thinking we’ve heard to further advance in how they collect, analyze, and interpret patient perspectives throughout drug development.


I think this series also empowers patient groups to actually take things in their own hands. If there is a disease where we don’t have endpoints, there is limited interest from companies because a drug development pathway is not clear or we don’t understand the disease, we don’t understand the symptoms. An advocacy organization or any organization who is interested can actually take this information and systematically come up with what’s the endpoint that we want to measure here and really drive the development for that condition. And we are actually seeing some patient groups actually writing guidance documents, and this has been in the public domain as well, where they’re really empowered and they’re using these guidelines and encouragement and empowerment from the agency to do that.

You know, within AstraZeneca, I joined about eight months ago, I really credit FDA and their proactiveness in raising awareness about patient-focused drug development. Let me give you an example. I was in a meeting about a couple of months ago, and my supervisor and I are presenting to clinical development colleagues. I think they wanted to know more about PRO, so we did a little bit of a workshop and then we prepped slides about why they are important. In the first two minutes I get stopped by the head of clinical development, saying, we don’t want to know what—these things are important, we know that, don’t tell us that, you can skip to slide number 10 that talks about how do we actually integrate this in our trials. So the recognition from within companies, some of the key decision makers, how important these things are, I was a little surprised. So it’s not about whether we should collect patient data, patient outcomes in trials, it’s more like how do we do it, that’s the question now. And how do you advance the science of patient input, not just PROs but also other things that I think TJ was alluding to earlier. Trial design, I think some of the people are questioning about it as well, what is appropriate trial design? Should we have patients’ input in that. What about endpoint selection, what do patients care about. Is survival important? Absolutely. What about quality of life, is that an important aspect.

So those are areas where outside of this PRO, I think patient input can truly make a big difference in addition to the benefit risk assessment for a particular treatment option that’s being developed and possibly submitted to the agency.

While supportive of FDA’s efforts, engagement between agency and stakeholders, including eCOA companies such as CRF Health, I think is important to really realize the success of PFDD. I think we will need enhanced communication pathways to really, once this PFDD initiative is being integrated into companies, not just big companies like AstraZeneca but also a lot of small companies, I think there’ll be a lot of questions. A company like AstraZeneca, large organizations, they have PRO expertise to support this. But there’ll be small companies who don’t have that, and they’re going to have a lot of questions. How do we do this. What do we do. What do we mean by patient-focused drug development. What is a PRO measure. That may not be a question but it’s going to require more communication probably as the questions are not whether to have a PRO or how do we do it and what do we do.

I think patient experience is a broad concept, as outlined in the guidance documents and also in the various communication with the agency. But I think clarity regarding specific standards for the collection of patient-focused data is in accordance with what’s the intended purpose, what’s the intended use, could be helpful for study planning. From where I sit, we have to make decisions about what’s our end goal, I guess, what are we trying to do here. Is this going to be a primary endpoint, a secondary endpoint. What are the evidentiary considerations, we have to plan these things in advance so we are able to meet the agency’s expectations and be able to submit the data that’s needed for other product approval, for labeling, for risk and benefit assessments, etc.

I think regulatory guidance and clarity around application of digital health tools within PFDD will be needed to really leverage the innovation that we are seeing in technology to advance drug development. And I’m referring to wearable devices, for example. How do we leverage those and integrate with the patient outcome measures in trials to really harness that objective way of assessing patient’s activities, for example. It could even be vital signs, body temperature for example.


So I think that clarity is probably needed, and one should not take this comment as a criticism. I think the agency is already thinking about this thing. If you were at the meeting, some of the questions that they were asking, they were actually asking feedback from public, from industry, from other stakeholders, how do we do this so they can actually meet the goals and needs of the broader public.

This is the way I see PFDD. I think eCOA solution need is already increasing, as I think Bill had in his slide, by 20% or however much it is in numbers. And it’s also going to increase in complexity with further integration of PFDD. I’m a big fan of ePRO, I think it’s a really great way to collect data that you reliably and you have confidence and you have very good compliance rate. I think that’s critical and that’s what the agency expects from the PFDD that you have a high compliance so you can actually interpret the data, interpret the results and have confidence in that. So I’m actually not going to talk about eCOA benefits because I think most of you guys know those. I think that’s the bread and butter of what you do and we really rely on your expertise in the area. I think there’ll be a lot more questions about complexity. I’m in oncology area where trial designs are just getting complicated. You have a new [unclear 21:43] phase, then you get into you have a surgery and there is a [unclear 21:49 and then they get followed up after their treatment. How do you design a technology solution where you have a high compliance at three or four years down the road? And what about scheduled assessments, something that I’m sure many of you guys have dealt with when you’re talking to your clients. They can get a little complicated, and I miss some of those 12-week trials. When I was an agent reviewing those, those are 12 weeks. When you’re talking about trials that are two, three, four years long trials, and I think we’re getting expectations to run more data not just for the regulatory agency but also payers as well. So we need this data and we need to collect this data so we have confidence in them.

And I think, going future down the road, I was actually at a grant round recently, and the topic was decentralized trials. And I think my comment was, we are already doing that with eCOAs. I think those are kind of decentralized, sort of element of decentralized trial, a patient actually providing the information from home via questionnaire. I think what you’ll be asked in the future is actually not just questionnaires but how do we—as I was saying earlier, how do we collect patients’ body temperature, how do we collect patients’ breathing rate, how do you collect that along with in the same device that they are actually using to complete PRO questionnaires. So you know, that scenario of complexity.

Now another thing I know that will be another topic in the next topic about bring your own device. You know, what do you do if you’re running a trial, global study, where a patient says, well I don’t want to use my own device in the middle of the trial. Are you going to just completely stop collecting the PRO data at that point or are you going to offer a provisional device? And how are you going to handle the data? We hear from the agency and the recent guidance that minimize the modalities you’re going to use. So is that really a patient-centered approach where you’re kind of forcing a patient to use one or the other method? So I think things like those we need to think about as we need to think about to integrate and I think we’re going to look up to other eCOA providers to provide solutions because I think we really rely on you guys in that sense.

So I think the need for eCOA solutions is going to go up. I think we’re just starting. So most of you here, I think your job security is pretty high.

In summary, PFDD, patient-focused drug development, is changing the drug development landscape in a positive way by putting the patient at the center of drug development. This is really an amazing change, probably, in the past ten years since the PRO guidance that came out in 2009. The question we hear within industry is, how do we do this. It’s not about whether we should do it or not. The guidance series is really paving the path to incorporate patient voice systematically with scientific rigor, I think that’s really critical, in drug development and regulatory decision making. And as I mentioned, I think demand for eCOA solutions is going to increase with PFDD integration throughout drug development cycles across industry.

With that, I conclude my presentation. Thank you for your attention. Any questions?


Great presentation, Nikunj you talked about patient experience being a broad concept. So the fact that patient experience is subjective and standards are objective, do you have any thoughts on how you essentially bridge that gap and translate what’s subjective into something objective like standards? Any perspectives on that?


Well, I think patient experience is broad, right, I think it involves so many things in a person’s life. We cannot measure everything possibly in a clinical trial probably. And can we even show a change in person’s certain aspect that they care about, for example productivity. We may see that over time, but can you actually capture that within a one-year or two-year trial, it’s kind of difficult to do that. So by standard, what I was alluding to, let’s say our goal here is to use a PRO measure or other CRO-type measure as a primary endpoint. What are the expectations for me as a sponsor to provide the level of evidence to convince, to show that the tool we’re using is actually a fit for purpose tool. Now, what about, we have a—we’re using survival as a primary endpoint. I think it’s a great endpoint most patient-oriented endpoint you’re ever going to get. And using PRO as a secondary endpoint, maybe not even key secondary endpoint. And you want to show how a patient is function, how a patient’s quality of life is being impacted. What level of evidence would be needed for the agency. There are two different scenarios. I think a little clarity around that would maybe be helpful I would say. But you know, the agency is probably working on that, I’m sure.


Great, well Nikunj, thank you very much.

[END AT 27:26]

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