Presented by Diane deBruin and Benoit Arnould, Mapi Group
The landscape of Patient-Reported Outcomes measurement is changing. Learn more about the facts, events, and trends from Mapi. Get a top-level understanding of the Patient-Centered Outcomes environment for safe and wise decisions regarding where to invest and when to innovate.
Other topics covered include: regulators and payor expectations from the pharma industry (do they want more science, or less?); investing on measurement; review of the prior dynamic on Patient-Reported Outcomes claims; interpreting the recent changes affecting former SEALD group and the newly released pilot compendium; method/preference trends regarding disease areas (Oncology, CNS, Rare Diseases…); and the pharma industry PRO resources organization.
Thank you, Paul, and thank you for inviting us today for this interesting and lively meeting. So I’m glad to have an opportunity to share that topic with you, and it’s very timely coming after Ari’s review on labeling claims.
As we see, there are a lot of question marks and especially a kind of skepticism in the industry about, okay is it really about the patients or is it just a kind of mantra with no application in reality of development. I will try to identify a couple of facts and trends that can help you and us understand where we are in this rapidly evolving world of patient-centric research.
So I’m presenting that with Diane today, so we’re very pleased to be with you. Diane is a specialist of a regulatory perspective. And we are enjoying ourselves working together as I bring the PRO perspective and that is a very complementary team. I also have to thank a couple of colleagues of mine who have helped prepare the data I’m presenting today, namely Catherine Acquadro and Isabelle Saffe from Mapi.
As a starting point, I’d like to identify what I have selected as what could be the most important facts in terms of patient-centred outcomes research and patient centricity of the decade. And that is the leading role of the group of parents of patients who have taken the initiative of telling FDA how research should be conducted to identify innovative drugs to help cure or help relieve or alleviate the condition of their children with muscular dystrophy. And three parents taking the lead, not only in terms of advocacy and saying we want that, we need something here, not only in terms of public relations and pressure on the industry and on the administration, but also in terms of taking the scientific lead, saying okay, this is how we want benefit risk to be assessed, that’s something which is very new and very interesting, and very promising, I believe. And that is an outcome of a long evolution that started a couple of decades ago. And I’d like you outline for you a couple of events or changes that I think have marked a big difference between what was the field of qualitative creative research three decades ago and where we are today.
We have moved in these couple of decades from quality of life, a very conceptual idea, a very much marketing idea, to jargon and very technical things like clinical outcome assessments. That’s a big move, move to jargon. We also have increased the standards in terms of sites. The free style that has presided in some labeling claims in the ‘90s is today over. It’s much more controlled than it was. We also have seen an interesting move of the horizon of science. The horizon of science was, three decades ago, registration. It moved progressively to market access, and now it’s moving to prescription, to have a drug adopted by prescribers and patients. Marketing has a role to play, but everybody wants to see evidence. And that’s an important evolution. And we also have, I’ve seen, an evolution from functional disease to other kinds of disease which are the priority of industry today, so a shift in the focus of industry has also occurred during this period. And also a shift in the business model of the industry from blockbusters to rare disease. And that is a big change as well. And last but not least, kind of around the clock, it has taken three decades to explain to doctors, forget your clinical case studies, we don’t want to see clinical case studies, we want to see evidence-based. And now we say, okay back to patients. Where is the patient? When and where did it disappear? So back to patient, patient centricity, personalized medicine, that’s after the secure of evidence, back to something that is the reality of individuals. And that’s also very important for us.
So what we try to do now is to kind of share a couple of other trends, and you will see data that are close to but not identical to those presented by Ari. An interesting contrast sometimes. But also, facts and trends about other elements that I’ve selected as being probably informative for those who have to design strategies for new compounds so as to have to support their strategies and to create evidence. One of the things that I think that these facts can inform the discussion is, are we going toward more science in terms of patient-reported outcomes, or less science. Is investment worse, having in this domain, is it really, to have—how do you word it—when you pay attention genuinely and with good scientific levels to the patient perspective. At the end of the day, all the objectives of that discussion is to try to give you clues on how to fine tune and to position this investment to make sure that the time and money allocated to evidence generation about patient benefit is well allocated.
And after that, I’ll try to be concise enough to not take the time that is for my colleague to discuss claims and her specialty of how to interact with FDA to have an optimization of the outcomes of your disease.
So first, another discussion about the impact of FDA guidance. Not exactly the same method, probably because there are some contrasts in some of the figures here as compared to what Ari has shared with you. The outcome of this comparison on the period 2000-2012, comparison of PRO claims, is that overall it is extremely stable. We don’t see a big impact of the FDA guidance on what was the proportion of claims in the file of new drugs, and what was the impact of this on the difference between the quality of life and symptoms, no influence neither. Quality of life has always been very low. Symptoms have always been the essential part of claims counted by FDA, no change.
More recently—and this is a comparison of FDA and EMA claims—what happened more recently, nothing clearly indicating a big change. Consistency in trends with what Ari has shown before, which is a slow decrease maybe. If it is interpretable or not, given the figures, I’m not sure. But at least this is consistent across the two parts of the Atlantic. And certainly less driven by the disease that has been very active, rather than by a difference in the way agencies have conducted their reviews.
What other learnings or lessons we can have from this period. The first thing is, PROs were more frequently used as secondary endpoints, while ClinROs were most frequently used as primary endpoints, as PerfOs were. ObsROs were used either way. And an interesting point on composites, which is obviously composite were essentially primary endpoints, that’s why they are designed as composite, that’s their role. They are frequently not considered when we speak about PROs, but most composites are PROs in part. So that is something that I will come back to a little bit afterward.
Which instrument. So the key point here is that a large majority of PROs that have supported claims were designed specifically for a study or for a drug or for a strategy. A lot of them were diaries. In the remaining part, we have an important part of a very well established legacy instrument. And what is interesting here is the contrast between EMA and FDA. And this shows that FDA is really very much on a specifically designed symptom scale used as diaries, EMA is much more inclined to accept legacy instruments with good validation status.
Another point on composite endpoints, I really think that this is neglected in how we consider the influence of PROs on labels. Most of the composite endpoints are a combination of a PRO with something different. PRO and ClinRO; PRO and performance outcome; or PRO, ClinRO, and biomarker. Another interesting point about composites is that this is very much an approach driven by division. Most of these composites are in the rheumatological area. And one interesting question for the future is why can’t we replicate this model to other areas, where we definitely need to have not only biomarkers as that endpoint, not only a ClinRO, but also confirmation by the patient of the benefits they receive from their drug.
Other facts of interest. One thing that has happened in the recent years is the multiplication of stakeholders and the complexification of the strategy for the drug makers. They have to convince a lot of different stakeholders, to some extent, that the chance for people to consider the patient centricity is essentialessential because the common point between all these people is how they can validly define the benefit-risk from a patient perspective.
The question is, do they want more science or less. My perspective is that they want less methodology and jargon, and they want better clinical stories and more explanation, more interpretation, something that can be communicated and distributed to clinicians and also to patients.
Another fact that I’ve selected as important is we frequently are driven by the desire to have positive claims. We tend to forget that an essential role of PRO—patient-reported outcomes—is also to support data, to convince people, and to consolidate a dossier. And here, for example, we see the importance of language in communication. And the lack of evidence supporting the use of the language chosen has led to a reduction of the adverts that were proposed here.
Another example here is the lack of data to support the idea that the benefit in terms of survival was not obtained at the cost of dramatic impairment in the quality of life of patients in cancer. These data were not available, and because they were not available, the agency has rejected the application. It’s not only the perspective of the regulator, it’s also the perspective of the payer to say we don’t have enough evidence in terms of patient benefit. We know that NICE is giving the value of a drug based on quality. But they also look at other data. And if they don’t have data saying, okay this drug is safe enough, it respects the integrity of the physical body and the life of patients, if they don’t see that data, they might have adverse reactions right here.
Another point is, we are frequently asked what is the value for payers of presenting them good PRO data. And we do not have to say, okay sorry, no evidence of that. The only counterpart, or the only explicit rewarding by payers based on the patient perspective is the question of economics, and that is addressed with qualities and utilities. The value of five points on a psychometric scale doesn’t exist, I don’t expect a payer to write that on a piece of paper. But the value in terms of convincing, and the value in terms of going beyond market access to market adoption, is great. To convince a prescriber to choose between drug A and drug B, if you have one that has evidence of patient benefit, this drug has much more chance to have good market shares than the other one. And that’s what’s demonstrated in this very interesting research work.
So what has happened and how can we interpret these trends. Fifteen years’ history on labeling claims, disappointing or good things. Stability, that’s clear. Is it still worth investing? Yes. More than ever it is worth investing. Investing carefully for evidence generation, for the purpose of being supportive or for the purpose of being defensive, or for the purpose of differentiating. That is more important than ever.
I’ve collected the kind of series of very different things that I’d like to share with you before ending my talk. And I think these are extremely important to consider, because they probably have signals of important things changing. One is in fact is I say the end of the period of great influence of the FDA guidance. We are moving to another era, and that has been marked by a recent meeting, one year ago. One of the—another indicator of this change is the split of the SEALD group, which probably is also a way to communicate that a review division has an important word to say in terms of PRO labeling claims. Another thing is about C-Path and drug development tool and qualification. Yes, there are some instruments that are moving along this way, with some success, but still there is a clear and shared understanding that these ways don’t solve the issue of developing and rating scales in a reasonable time at a reasonable price to support good decisions. So the business model of development of PROs still is problematic for us. Another important fact is these PRO-CTCAE. For the first time we see that the measurement of the patient perspective is going beyond benefit to also be used for measurement of harm. I mentioned the Duchenne Muscular Dystrophy thing as a matter of fact. The pilot compendium, that’s an interesting thing that’s new. We all wait for maturation and expansion of this. We still don’t know exactly where it will lead, but it’s interesting. The PROMIS, as has been said, there is a door opened by FDA to a renovation in how to use instruments and PROMIS is one of them. Rare disease, the question around rare disease is not solved, how to assess patient perspective in rare disease. That’s a big question mark that still needs to be solved. Preferences and discrete choice experiments have emerged in the landscape as also something very interesting that could develop in the next years.
The question of BYOD, as discussed today, is probably also something that is changing rapidly. A big question mark, which is paediatrics, we don't identify that we need something. We sill have nothing, or almost nothing, that’s very interesting. And also something changing in the landscape, which is new stakeholders for pharma industries which are in the US with the ACOs that are likely to influence rapidly how the benefit for patients is documented. Mixed method research, rapidly evolving field with high potential. And the kind of messages coming from regulators saying that they would like to expand somewhat how the benefit is defined for patients. That’s good for oncology, with an important door opening to taking the caregiver perception, and from EMA with an opening door to assessment of convenience and organization of care.
And I’m done, and Diane it’s your turn.
Okay, so obviously it’s very important to have clear and concise interactions with the FDA so that any studies that you conduct and PROs that are evaluated are acceptable by the agency so that you can, one, put it in a label, or two, use it in advertising.
Obviously the purpose of your Phase II and Phase III studies are to ensure that your primary and secondary outcomes, whether they include patient-reported outcomes, clinician-reported outcomes, observer-reported outcomes, or performance outcomes, are qualified and evaluated to support the regulatory decision making. The outcomes can be assessed as primary or secondary outcomes, and these were discussed briefly before. One of the concerns with using PROs, as a secondary outcome or an exploratory outcome, is whether or not when they are evaluated and they are deemed to show significance, is how are they rank ordered in the secondary outcome. If you lose on one of your first secondary outcomes, you can’t use anything that has shown significance in your label if it’s not rank ordered appropriately. And that’s obviously one of the concerns with the agency as you design your studies, is there a potential for it to fail and knock out all your other secondary outcomes. So that’s usually one of the early discussion points that we have with the development of the clinical trials and the establishment of the protocols.
There is a lot of old legacy outcomes, PROS, that were not formally qualified. FDA has said that these can continue to be used in studies. And the main purpose is to ensure that any of the outcomes that are evaluated allow for the appropriate interpretation and regulatory decision making. Will they approve your drug or not, will they allow the claim in your label. One of the benefits over the last couple of years is the fact that FDA has actually published the compendium. The compendium that was published, or the pilot compendium that was put on the website in December of 2014, covered labels that were approved from 2003 to 2014. Last year, it was updated to also include the Drug Development Tool COA Qualification Program, and what’s currently being evaluated by the agency. This is a great resource as you’re developing your clinical trials to actually go and search into that compendium, by the review division and by the indication, to see what FDA would accept as legacy PROs and what they are currently evaluating.
For example, in the compendium, they have the two tools for COPD, where they look at the St. George Respiratory Questionnaire as a patient-reported outcome but they also require the observed outcome of FEV1. So you must demonstrate success in both of those outcomes—well, observed success in FEV1 for your drug to be approved, but then also they look at the evaluation of the St. George Questionnaire. For asthma, they are working with the Critical Path Institute to qualify and look at the PRO outcome for asthma symptoms.
Interestingly the also recently published the COPD guidelines in May of 2015, and although the legacy PROs are acceptable for use, they also evaluate these over time as new information becomes available. So they provide additional information about the changes in the St. George Respiratory Questionnaire, and how it’s changed—there’s two questionnaires, a 50-item questionnaire and a shorter 40-item questionnaire—but they also state that not all versions have equivalent validation information. So this is something that you would need to go back and discuss with the agency as you choose your specific questionnaires or if there has been any modifications over time.
There are a number of different options to discuss qualifications and COAs with the agency. The Critical Path Innovation Meetings, Drug Development Tool Qualification Program, and then obviously your specific drug development meetings with the agency.
The Critical Path Innovation Meetings are really for discussion of clinical outcomes in the context outside of a specific drug development program. And this is to get initial feedback and understanding of what would be needed to qualify an outcome. And they will answer questions that would allow the consortium or the individual company to move that outcome assessment into the Drug Development Tool Qualification Program.
When this was first implemented, there’s been 19 meetings held from June of 2013 to March of 2016, and two of those 19 meetings actually covered PROs. The ultimate result is to allow those outcomes to be used for regulatory decision making, to support the market approval, or for labeling claims. The CPIM meetings do not result in any formal agreements. They’re more discussions that would allow you to progress the development of your outcome assessment. And it’s actually not a forum for ongoing discussions with the agency. They hope that you would then progress into the next stage, which would be the Drug Development Tool Qualification Program.
This is a collaborative setting. A lot of the initial discussions are through working groups or consortia. FDA asks that any information on the qualification program is made public. However, only those companies that submitted a tool for qualification and has agreed to make it public will be listed on the FDA website. If the tool is qualified, the information will be made public, but the tool is still considered to be proprietary, and that would allow the owners of the tool or the company that has developed it to still allow charging a reasonable amount for the use of that tool.
There are over 30, about 33, outcome assessments that are currently going through qualification. Twenty-eight have to do with PROs, four with performance objectives, and one for Gaucher disease, they haven’t yet determined which category it falls in. FDA does have a specific guidance on how to take a program forward for qualification, what’s specifically required in your letter of intent, what’s needed for meetings, what’s required for the briefing packages, very specific and standardized on how to interact for a qualification program.
An example of a consortium that has been working under the DDT Qualification Program is the Clinical Path Institute, and there’s a number of PROs for different indications that they’re working on. They also hold—since this is a public process—they’ve been holding annual workshops. The sixth workshop was most recently held in April of 2016 and that includes industry sponsors, obviously the C-Path, FDA, and then outside collaborators who would be, in most instances, the collaborators or the builders of the tools. They’re working on a number of PROs for asthma, cognition, depression, irritable bowel syndrome, lung cancer, rheumatoid arthritis.
As Benoit mentioned, one of the tools that are being developed by a consortium is also posted on the compendium. And this indicates for Duchenne Muscular Dystrophy, that the submitter was the Research Institute at Nationwide Children’s Hospital, and they’re in the process—or posted—a guidance document.
There are currently two tools—two outcomes—that have actually gone through formal qualification. As mentioned, this information is all public on the FDA website. The two tools that have progressed through the qualification, one is the EXACT tool. As indicated it’s made it through the next stage of qualification that allows it to be used as an evaluation of endpoints in Phase II clinical trials. And this is to measure the symptoms of acute bacterial exacerbation of chronic bronchitis in patients with COPD. There is also another tool that has partially been qualified, as the EXACT tool for pulmonary disease, respiratory symptoms in COPD. This was posted in March of 2016, and this is qualified for use in exploratory trials. So as it goes through their development program, it will be accepted for exploratory use Phase II studies, and then hopefully Phase III to support the market approval of the drug. That’s the ultimate outcome.
As mentioned, there is about 33 COAs that are being developed, or being reviewed within the qualification program. FDA is limited in their resources. Under PDUFA and the fact that companies pay under PDUFA for the review of their new drug applications, they pay anywhere from 1.5 to 2.5 million dollars for the review, that focuses the review staff on supporting the review of the drug applications. So one of the challenges that’s ongoing is, you have the clinical outcomes assessment staff at the FDA and they’re trying to work with the review division to qualify, to agree to the qualification of the drug development tools. However, there’s a resource constraint. So what they try to do is prioritize which applications they’re going to work on, and this provides some description of how they prioritize. Is there a critical measurement gap? Is a drug development program stopped? Does this represent an improvement over currently available tools? And at the bottom it’s: are the review division in clinical outcomes assessment staff resourced appropriately? Thirty-three tools, six years, various meetings, a pre-meeting before every meeting, a post-meeting after every meeting, an agreement on what discussions occurred and what they can state in a drug development program. It’s a significant amount of work, let alone taking on these extra initiatives constrains the agency’s resources. They have not defined how they prioritize but this is the evaluation of their prioritization process.
So if you’ve met with the agency in the Critical Path Initiative meetings, you’ve taken your drug through the drug development qualification program, or if you’re working on any modifications to legacy PROs, there’s always the standard drug development meetings. FDA has a guidance on PDUFA meetings. You can have a Type B/Type C meeting depending on where you are in your development, whether or not your program is stalled. You can discuss early on with the agency at your pre-IND your End of Phase II meetings, the discussion of any modifications to your tools, and then also the ongoing discussions through the review of your protocols, and specifically how these tools will be used.
So FDA has issued a number of guidance documents. The first one is the Patient-Reported Outcomes from 2009, specific guidelines on how the qualification process works. The guidance in 2014, Critical Path Innovation Meetings. And then the formal PDUFA meetings, standard meetings with the agency in your drug development program. So if you ever have any questions, the guidance documents are always helpful. Or you can speak with your regulatory department.
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