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Transcript:
Date: 8/29/2007
In this episode, I meet with Jeff Trotter, Senior Vice President, Icon Clinical Research’s Life Cycle Sciences Group; formerly Ovation Research Group. We talk about the brave new world in post-approval research and how the industry can respond to this changing landscape.
I’m your host, Dan Limbach, producer of the PharmaVOICE Webcast Network.
Dan: Welcome to the program, Jeff. Let’s get right down to it. What are the critical issues underscoring the need for data on real world value and safety and why is there a new paradigm needed for a responsible and opportunistic industry response?
Jeff: Well in terms of the critical issues, I think the reality is that data from pre-approval randomized clinical trials fall short in terms of predicting what’s going to happen in the post-approval environment. The reality is that the conditions under which drugs are evaluated for approval are not the conditions under which they’re actually being used. One of the better metaphors I saw recently was the concept of a test track for automobiles relative to actual traffic conditions and obviously, these are far different.
From a patient perspective we’ve got, in the real world, patients that are noncompliant with the drugs they take. They’ve got comorbidities, other conditions that would have been excluded from clinical trials, they’re taking multiple drugs, they’re basically being managed under real world conditions, and in many cases, physicians aren’t undertaking the testing, the extensive testing, the diagnostic or confirmatory tests that they might in a randomized clinical trial where those are mandated procedures.
So the real world is just really different, and we need data on these conditions. Bottom line is real world studies require a specialized design, and so as to be a good return on investment for their sponsors, they need to be designed and undertaken in a very collaborative manner, which can be a very challenging aspect for an industry that’s organized for practices really that are decades old. The concept of a new paradigm is that industry has a responsibility to its shareholders certainly, but also as kind of a citizen of the healthcare industry and the healthcare community, the industry needs to document and certainly monitor how the products are actually performing in this real world environment. If done correctly, it’s a great opportunity for the industry to achieve its business goals at the same time to do studies that are scientific, to do studies that are strategic, to do studies that are cost effective.
Again, the critical issues are that we need data on what’s happening in the real world because that’s really where drugs are used and we need to operationalize the studies to document the real world differently.
Dan: That’s very interesting. Let’s talk about the post-approval landscape. How has it changed and what role do patient outcomes, safety surveillance and/or risk management play in this new environment?
Jeff: Well there are a lot of things happening in the new environment we’re in today. The fundamental thing that’s happened over the last 20-30 years is that our scientific methods are better. The understanding of the information that we have, the approaches that we have to interpret information are better. So that’s a foundation that is improving the science of where we are with research studies.
But other things are happening along the way. We’ve got patient empowerment. Patients are more part of the decision-making process than they’ve ever been. As a result, you see a lot more direct to consumer advertisement in the industry. In general, there is better communication on really all sides – patients and physicians; better awareness of diseases that, in the past, may have been kind of below the radar screen and fundamentally, that’s an increased opportunity to alleviate suffering; to achieve some cures in patient care.
So patients are very well aware of the opportunity to reach out and access different treatments, different drugs, different devices. That, at the same time, suggests a greater focus on patient quality of life and lifestyle; it’s not just is the operation successful? Does the patient’s lifestyle and quality of life really improve? At the same time, there’s economic factors, and over the last 20 or 30 years, we’ve recognized that we can’t afford everything in healthcare.
So we’ve got these competing factors. We want to improve the effectiveness of drugs and devices, patients want to improve quality of life. At the same time, we can’t afford everything. This is kind of marked by an every 20 year or so phenomenon, in terms of how these changes in the environment are reflected in regulation. Forty years or so ago Medicare, obviously in 1965, was a big revolution for the management of public health. Twenty years ago, or so, prospective payment came about in the United States, changing the way healthcare was reimbursed such that essentially, there was fixed prices for healthcare services, which required an emphasis on the concept of cost effectiveness – how can we achieve the same outcome, the same level of quality, but at a more manageable cost? And now where we are today, we’ve got the spectra of new regulation. Certainly in some countries, regulation has already taken root where products aren’t just released, there are conditional approvals where data has to be compiled to document how the product is actually working in the marketplace. There’s a perception and, to some extent, a reality of unfulfilled commitments for post marketing surveillance programs, and I think some of the reasons underlying that is that again, these programs are very difficult to undertake. They’re not a snap of the fingers. Companies can’t apply the same approaches that they have to pre-approval studies to undertaking these post-approval studies.
In many cases, companies will grapple with this issue for a number of years before really adopting a new approach. The role of outcomes and safety surveillance and risk management is that these are the critical measures in the real world. The quest used to be for documentation on safety and efficacy, for pre-approval safety and efficacy; that was really the end of the marathon for drug and device companies, to document that, to get the product approved and then achieve all the commercial endpoints they want. Now I think what’s happened is that the industry has recognized that there is a few more miles to go on this marathon and many companies just don’t have the energy to really develop programs that can take them the additional mileage required to document what works, is it worth it, what positively impacts a patient’s quality of life, what safety issues may be out there; all of these are real world issues and real world questions that need to be answered.
Dan: Those are all very important issues Jeff, and there are obviously a lot of stakeholders here. So following up with that, why do post-approval prospective observational research require a different operational context and approach?
Jeff: First of all, one day we may not even need as much prospective study with the rise of automated medical records, electronic medical records. One day, we will have all this information at our fingertips to be able to mine information to find out, again, what really works, what patients value. But the reality is the systems really aren’t where they need to be today, and it’s probably going to be 10-15, maybe even 20 years before we get systems talking to each other; systems that have the kind of data that’s necessary to really answer these fundamental questions.
Where we are today is that we’re dealing with prospective studies, observational studies, studies that really require us to have as light a footprint as possible. We can’t use the same controls we use in pre-approval clinical research because that creates an artificial environment and we’re trying to find out what really happens, again, in the real world. We can’t have controls, we can’t have placebo, for example, as one treatment arm because patients are treated and that’s just not reality.
While there probably isn’t ever a perfectly observational study, any time you’re examining a situation, there’s always going to be some kind of impact; some of it discernible, some of it not but, as much as possible, we need to try to approach this with a very light touch; with a very light footprint for how we collect data, with protocols that are really “only protocols,” if you will, they don’t mandate particularly how a disease should be treated or what procedures should be undertaken in this research study. They really only document the kind of information we’re trying to collect. Therefore, the operational mandate underlying how a study is run needs to change.
For example, in a randomized clinical trial, we would have a protocol that would dictate how this experiment would be run and you would have monitors out there, determining how well a site has adhered to the protocol. In the real world, in an observational study, obviously you can’t do that again, because there is no protocol that has procedures that you’re adhering to. So the whole imprimatur for monitoring changes. Data quality is another issue that has to be looked at from a different perspective, particularly when we’re capturing information directly from patients on quality of life. You really can’t go back to the patient and say well, did you really mean that? You can’t validate the information the same way as you would in a more experimental clinical trial. Often you’ve got thousands of patients to weed out some of the noise you might see in observational studies and therefore, you have different approaches to how you recruit the sites, different approaches to how you recruit the patients.
The other factor is that real world studies are again, done in a real world environment. You’re probably not going to be enrolling clinical trialists, physicians that have a lot of experience doing pre-approval studies because you really want to find out what happens in more of a nonacademic, more of an actual practice setting. So you’ve got to deal with physicians in a different way; a kinder, gentler approach is needed to make sure they understand what’s involved in the study, how important the information is that we’re collecting; how serious we are about the analyses and again, to run it in a different fashion.
Dan: So in your expert opinion, Jeff, what do companies need to consider when designing and undertaking real world, prospective observational studies that include safety and other endpoints?
Jeff: I think the opportunity is to strive to address safety, which is an important issue obviously, and these endpoints, like value; whether it’s cost effectiveness, whether it’s quality of life, whether it’s real world clinical effectiveness. All of these things are important and to the extent that all these issues can be addressed in one single study without over-engineering the study. This is going to be a good strategy, good science and cost effective from the sponsor’s standpoint. The problem is that rarely do the people responsible for safety surveillance issues, and those concerned about issues like value and cost effectiveness, rarely do they hang out together in pharmaceutical and device companies. The challenge is most companies aren’t optimally organized to undertake this kind of research.
So the new paradigm is that the company really must make a public commitment to support ongoing post-approval research. The industry really, in my opinion, shouldn’t be waiting for legislation; they should be taking the opportunity to be proactive, to capture the opportunity, to really demonstrate their commitment to their products. The companies must recognize that post-approval research is both the responsibility and, if done right, a great opportunity to contribute to science, to support the safeguarding of public health and to promote the use of its cost effective products again, assuming that they can be documented as such. One of the key factors is that the companies must assemble multidisciplinary teams to contribute their respective expertise to what essentially is an entirely different animal, an entirely different type of study, an observational study.
Generally, we see contributions from medical affairs, from pharmacovigilance, clinical operations, marketing, product management, legal and regulatory, epidemiology and in particular, from outcomes research or health economics departments who actually, I think, are in a very good position to lead this charge. But again, when I mention all these different disciplines, these are functions within companies that rarely have gotten together but we’re seeing that that is an essential aspect, so that everybody can share their particular expertise. No one department can rule the day, it has to be a well orchestrated collaboration with clear goals and strategies, and ultimately the goal of the group is to contribute, again, their respective expertise to the design and execution of real world post approval research.
Dan: There’s obviously still a lot of work to do. Paint us a picture of what this arena will look like, say, five years from now.
Jeff: Well, I think five years from now, all that’s kind of swirling around today, as far as regulations concerning the post-approval commitments and the post-approval mandates that companies have to adhere to will be in place. There’ll be a different regulatory environment, an environment where post marketing commitments will have to be undertaken and there’ll be keys to enforce these commitments. But I think also companies will have adopted this kind of new paradigm and looked at things more strategically. They won’t just wait for the legislative mandate, they won’t wait for the mandate from a regulatory agency; they will take the opportunity to accommodate these endpoints within their studies. Again, safety endpoints, as well as other endpoints, and proactively establish these designs with the goal of capturing what’s out there, capturing what’s happening in the real world and truly documenting how their products perform. Again, I think the major difference between now and five years from now is that, in most cases, five years from now, that will actually be a requirement, to submit information after the product has been on the market for a few years; whereas now, it’s really not a requirement other than perhaps a few countries in Europe. But I think we’ll see that in the US. I think actually it’s a good thing, it really is a more formal approach to documenting what tends to be a relatively squishy issue.
So I think we’ll see much more proactiveness on companies that are really concerned about maintaining their business advantage, but also being good, responsible citizens of the healthcare community.
Dan: Thank you Jeff, for sharing your insights and thought leadership on these important post-approval issues.
Jeff: Thank you, Dan.
Dan: That wraps up this episode. If you would like to learn more about post-approval or other clinical research, visit www.ovation.org.
If you have any feedback on this episode, send an email to feedback@pharmavoice.com, and don’t forget to check out our other podcast episodes at www.pharmavoice.com/podcasts.
Until next time, I’m Dan Limbach.
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