Emerging Regions - Alan Braverman
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PATIENT ENROLLMENT INTO CHALLENGING CLINICAL TRIALS SUCCESSFUL INCORPORATION OF EMERGING REGIONS
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Transcript of Emerging Regions - Alan Braverman
PATIENT ENROLLMENT INTO CHALLENGING CLINICAL TRIALS
SUCCESSFUL INCORPORATION OF EMERGING REGIONS
Impatient About Patient Enrollment® Slide 2
POOR PATIENT ENROLLMENT IS THE INDUSTRY‘S BIGGEST PROBLEM
85% of trials are behind schedule and the main reason is slow enrollment; only 6% of trials finish on time (CenterWatch)
Investigators and Project Managers are too optimistic about patient enrollment at the study start
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Presentation Notes
Poor Patient Enrollment is the Industry‘s biggest problem Multiple sources say that 80 to 90 percent of all clinical trials fall behind schedule due to poor patient enrollment. Curiously enough these depressing statistics have been out there for close to a decade now. They were first published in the late 90s and since then remained stable plus or minus a couple percent. That obviously means that the underlying issues of poor patient enrollment remain largely unaddressed. One might get an impression that the issue of patient enrollment has become something akin to the proverbial elephant in the sitting room: here it is, big as life, sitting on the couch, taking up half the space we have, but we’d rather talk about getting new door fixtures or fancier wallpaper. Likewise in clinical trials, we may be raving about some new fascinating technology that can help cut the time to database lock by a week or two while at the same time our enrollment is 9 months behind schedule.
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THINGS DON’T GET EASIER
Complexity of clinical trials doubles every 5 years
Larger sample sizes
More demanding regulatory requirements
Unique study designs
Ever-growing competition
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Things don’t get easier Clinical trials have expanded in every possible dimension.� some run for close to 15 years some involve around 50,000 subjects and 8,000 trial sites some carry a price tag to the tune of 250 million dollars. More importantly, the intrinsic complexity of clinical research doubles every 5 years, which shouldn’t come as a surprise, as medical knowledge has been growing at about the same rate. The regulatory requirements are becoming more and more demanding and often times not necessarily compatible with real life or routine medical practice; we see more and more studies with unique protocol designs where there’s no way to rely on any kind of historical data for patient enrollment; the sheer number of clinical trials is growing every year, so competition is building up and in some regions of the world has reached horrendous proportions across pretty much all indications. To hope that given all of the above circumstances patient enrollment will straighten out by itself would be very short-sighted.
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FUNDAMENTAL REASONS FOR ENROLLMENT DELAYS
Poor Feasibility
Mismanaged Projects
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Fundamental Reasons for Enrollment Delays What are the main reasons for poor patient enrollment? Both sponsoring companies and CROs could probably come up with a long list of reasons, but if we were to name just the top two, you will probably agree that Fundamentally, clinical trials fail to meet their timelines either because their complexity was underestimated to begin with or because they were not adequately set up and/or managed. Broadly speaking, it’s poor feasibility or poor management, or both.
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STUDY FEASIBILITY
Overlooked complexities
Medical“granularity” of therapeutic indications resulting in smaller patient subpopulations that today’s protocols target
ClinicalHow well the protocol fits into the paradigm of routine medical practice
LogisticalRepresents half the battle in a clinical trial; can easily render a medically feasible study undoable
Regulatory
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FEASIBILITY EVALUATION BY WHOM? HOW? WHERE?
By Whom?By specialized Feasibility Staff / Full-time feasibility
expertsMedical expertsLogistical expertsLab expertsRegulatory experts
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FEASIBILITY EVALUATION BY WHOM? HOW? WHERE?
How?By performing an analysis of
Site Surveys
Historical enrollment achievements
Current competitive landscape
Influence of logistical, regulatory and clinical
complexities of a specific protocol
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FEASIBILITY EVALUATION WHO? HOW? WHERE?
Where?Keep the right balance of participating countries:
Enrolling
versus
Strategically important
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Feasibility: by whom?� Of course, there are more aspects to good feasibility, but I hope the overall message is abundantly clear: The times when feasibility could be assessed by CRAs or whoever-is-available are officially over. Likewise, enrollment estimates based solely on prior experience no longer work. Today, the feasibility assessment of a large complex project (and most of them are) represents a project in its own right, which should be coordinated by therapeutic area experts, obviously physicians, with input obtained from field practitioners (project managers), logisticians, and regulatory professionals. It takes time and effort and funding. Feasibility is a department. Feasibility: how? �What would constitute a good feasibility effort? We know the industry is very fond of Questionnaires, and indeed they are a good effective tool to strike a conversation with a site. Yet oftentimes, this is where feasibility ends, with a summary of the questionnaire data received by e-email of fax. Not good enough. In my company we strongly believe it “live” communications. You need to talk to the sites and if you ask them the right questions addressed in the context of all the competitive studies they will be involved in at the same time, you’ll all often find that by the end of the conversation the numbers are different – more balanced and more realistic. Then you go back look at your own historical data in this indication and maybe even with this site and sieve those numbers through even tighter filters. And if you take into account information on the competitive studies that is more or less publically available these days, this will give you an even more realistic number. Critical thinking is key to analyzing the site’s projections. And the more renowned and wanted by the industry this site is, the more critical the thinking needs to be. Which brings us to the next questions, where to look for sites? Feasibility: where?� There is no universal answer to the “Where?” question, of course. Depending on the indication, phase and current marketing status the call for countries will vary. What will not vary is the fact that no matter what the indication, phase or current marketing status, the study still needs to enroll patients within specified timelines. Most large, complicated studies that DO meet the enrollment timelines have one thing in common: a lot, if not most, patients were enrolled by sites in so-called emerging markets, be it Latin America, Asia-Pacific, Eastern Europe, or any combination of the above. These are the realities of today’s clinical research. The traditional countries of Western Europe and the US are of course regions of intrinsic marketing value for pharma companies. They are, however, not very good at enrolling patients. And there are regions, which, do not have the prescribing power of the biggest markets, yet can reliably enroll hundreds of thousands of patients and then some. I will not expand here on reasons why some regions enroll patients and some don’t, as enough has been said about this at various industry forums. I’m sure you all know what I’m talking about. Finding the right geographical mix is not easy, especially given the numerous conflicting interests one has to accommodate. Thought leaders of the big markets are often needed to be involved to render international credibility to large pivotal studies, but expectations regarding their enrollment capabilities should be tempered. At the same time, the huge recruitment potential of the emerging markets has to be harnessed, with a lot of effort invested into training, logistical support and closer monitoring.
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MAJOR EMERGING REGIONS
Impatient About Patient Enrollment® Slide 10
MISMANAGED PROJECTS
Unsubstantiated optimism
Poor communication
Presenter
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Mismanaged Projects� Let’s address the second largest reason for poor patient enrollment – mismanaged projects. PSI is frequently asked to rescue studies or take projects over from others, so we often find ourselves in a situation where we need to clean up. In other words we had a chance to come across some badly mismanaged project and draw some hopefully viable conclusions. If we were to summarize our observation and conclusion drawn by our sponsors interviewed for this talk, people seem to agree that it is Project Manager’s unsubstantiated optimism that often causes long-term problems. Optimist is a good thing, but in project management it needs to be based on something, preferably facts and figures. Too often Project Managers leave too many things to chance, hoping things will somehow sort themselves out. If we were to change just one thing in project management that could have a huge potential impact on improving patient enrollment it would be site management. Since most of site management is done through monitoring, it is site monitoring that needs to step up.
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SITE MONITORING
Investigators need help not old-style monitoring
CRAs must become versatile, better educated, better trained professionals
Adequate site support no longer fits into “once-standard every 6 to 8 weeks monitoring”
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Site Monitoring� The bar needs to be raised for site monitoring. The traditional monitoring tasks, such as source document verification, drug accountability, confirmation of proper consent procedures etc, are still high on the agenda. However, with clinical research evolving to a higher plane of sophistication, CRAs have more work to do. Any aspect of the trial outside of the site’s daily routine requires some serious handholding. And there are a lot of procedures in today’s protocols that have limited relevance to routine clinical practice. Someone needs to spend a considerable amount of time teaching the investigators to navigate CRFs and EDC systems, find solutions for those ECG transmitters that keep acting up all the time and of course someone has to help the good doctor master that asthma inhaler that has a built-in retinal scanner, while it takes exactly sixty puffs to deliver the right dosage. For CRAs to fit into the new paradigm of the 21st century clinical research, they ought to be better educated and better trained. Today’s monitor needs to be versatile, like a Swiss knife. They need to understand every aspect of the study and be excellent communicators able to find the right words, allegories and metaphors to bring their point across. They need to be able to anticipate problems at the site and deal with them proactively. They need to babysit the sites when the sites hit enrollment blocks, creating screening logs together, tracking every databased patient that may potentially become eligible in the coming weeks or months, following up on the status of these patients; and so on. By the same token, the once-standard assumption that sites can be adequately supported if monitored once every 6 to 8 weeks doesn’t work any more. If the industry wants to run larger and more complex studies, explore more endpoints and inevitably collect more data, the monitoring has to be given a chance to keep up by allocating more hours and, again, investing more time into training.
CASE STUDIES
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CASE STUDIES Let me now show you several case studies that completed patient enrollment this year. In those studies we tried as much as possible to implement the recommendation given above and let’s see if that worked. The slides will speak for themselves as they track a very simple and straightforward performance metric – actual enrollment vs planned enrollment. Just follow the blue line. XX CASE STUDIES FOLLOW, ENROLLMENT INTO ALL COMPLETED IN 2009.
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NSCLC, PHASE IIIACTUAL VS. PLANNED ENROLLMENT
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Title: A Randomized, Phase III Trial of ABI-007 and Carboplatin Compared with Taxol and Carboplatin as First-line Therapy in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC) Project IDCA031 # of sites45 # of pts724 GeomixRussia, Ukraine ClientAbraxis PMAlexander Moskalenko StatusTreatment/follow-up
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COLORECTAL CANCER, PHASE IIBACTUAL VS. PLANNED ENROLLMENT
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This phase IIb study in colorectal cancer had 22 sites in Europe and we managed to complete enrollment of 120 patients perfectly on time in February this year, even thought the regulatory start-up took longer due to the unavailability of the study drug. Project ID0501 # of pts176 (in total) GeomixRussia ClientPoniard PMDmitry Orlov StatusClosure
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AML, PHASE IIBACTUAL VS. PLANNED ENROLLMENT
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Project ID:SG033-0003 We are very proud of this study. Acute Myeloid Leukemia is not an easy indication, so it is only remarkable that we have managed to enroll 220 patients in this challenging indications ahead of schedule. We had 110 sites all across USA, Latin America and Europe. GeomixRussia, Romania, Ukraine, Bulgaria, Poland, Hungary, Lithuania, Austria, Serbia, Bosnia, USA ClientSeattle Genetics PMValery Matvienko/Yastrebov, Dmitry StatusTreatment/follow-up
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RENAL CELL CARCINOMA, PHASE IIIACTUAL VS. PLANNED ENROLLMENT
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Title: A Phase 3, Randomized, Controlled, Multi-Center, Open-Label Study to Compare Tivozanib (AV-951) to Sorafenib in Subjects with Advanced Renal Cell Carcinoma Project IDAV-951-09-301 # of sites51 # of pts385 GeomixBulgaria; Czech Republic; Hungary; Poland; Romania; Russia; Serbia; Ukraine ClientAVEO Pharmaceuticals, Inc. PMFirdavs Abdusamatov StatusTreatment/follow-up
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MULTIPLE SCLEROSIS, PHASE IIIACTUAL VS. PLANNED ENROLLMENT
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Title: A Phase 3, Randomized, Rater- and Dose-Blinded Study Comparing Two Annual Cycles of Intravenous Low- and High-Dose Alemtuzumab to Three-Times Weekly Subcutaneous Interferon Beta-1a (Rebif) in Patients with Relapsing-Remitting Multiple Sclerosis Who Have Relapsed On Therapy Project ID:CAMMS32400507 # of sites15 # of pts133 Client: Genzyme Corporation Geomix: Russia, Ukraine, Czech Republic, Poland PMJulia Smolina StatusTreatment/follow-up
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BREAST CANCER, PHASE IIACTUAL VS. PLANNED ENROLLMENT
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Project ID:AS1402-C-201 We ran this phase II study in the US, Western Europe and Eastern Europe and had 110 patients enrolled at 28 sites 4 months ahead of schedule GeomixRussia, Ukraine, Poland, France, US ClientAntisoma PMElena Yassievich StatusClosure
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COMMON FEATURES BEHIND THE CASE STUDIES
Good Sponsor/CRO rapportThorough feasibility performed by dedicated professionalsMaximum logistical supportGo-the-extra-mile project management and monitoringCorrect geographical placement: Be where the patients are!
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Common features uniting the case studies� Having given you a number of success stories, let me generalize by pointing out the common features uniting the case studies: Good rapport with the sponsor was essential. We enjoyed a trusting, mutually respectful relationship and the benefit of being able to discuss problems openly, as opposed to tiptoeing around them. No effort was spared in assessing the feasibility of the projects. Several years ago, our company set up a dedicated feasibility unit staffed with experienced physicians of various therapeutic backgrounds, lab experts, imaging specialists, logisticians, and regulatory advisors. This feasibility department has dedicated in all operational countries. Although these people do not normally generate billable hours, let me tell you: they existence pays. All-out logistical support was part of the project implementation strategy from the start. We are convinced that logistics represents half the battle in a clinical trial. Especially so if in your enrollment projections you heavily rely on patients from the emerging regions. This is why in some of the most difficult countries we employ dozens of dedicated logisticians. Again, this is an investment, but it pays off through reliable and predictable patient enrollment. These projects were closely managed and monitored and a great deal of effort was put into building effective, long-lasting relationships with the sites. Finally, the correct geographical placement was critical, where from the very beginning there was no confusion about the ultimate roles of different countries and realistic patient enrollment expectations went into the planning documents from day One. When all is said and done, we all need to go to where the patients are.
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CONTACT INFORMATION
Alan J Braverman, Pharm. D.PSI Suite 210500 Office Center DriveFort Washington, PA 19034+ (267) [email protected]
