1. What, in your opinion, is currently the single largest trend with respect to clinical trials?
MW: Increasing complexity is the biggest trend. Trials continue to grow bigger and more global. Regulation keeps expanding. Scientific and technological advancements make sophisticated new approaches possible which rarely turn out to be simpler. Meanwhile, there is a widespread recognition that clinical research is broken. It’s too expensive, and it’s time-consuming.
Many wonder why technology hasn’t been a more positive factor. It’s due, at least in part, to the predominance of "siloed" technologies -- a result of pharmaceutical companies purchasing individual products to support separated job functions for each stage of a trial. Recently, there is a growing appreciation for the idea that a unified Clinical Development Platform would go a long way towards improving the overall process. At BioClinica, we help our clients to manage these challenges and we believe that such a breakthrough would indeed help. We are already seeing change in the traditional purchase patterns… in our space, this is huge.
EM: It is the relentless pursue of increased productivity. This has two major components: greater speed and cost reduction. The clinical trial business has become a real industry, where each component of the delivery chain is working hard to make more with less, optimizing processes, like planning, recruitment, training, data capture and data management, etc, and scrutinizing costs at all levels in an unprecedented way. The result of those moves is that the "mom and pop" research site is moribund, the academic sites have to align their operating model with the industry in order to survive, and the professional research sites are dominating the field. And this is not true only in developed countries, but also in emerging regions, which have become a preferential place for clinical studies, and which are inserted in this competitive world right from the start.
NA: Late phase clinical research has become a growing focus for regulators, CROs and biopharmaceutical and medical device companies. Increasing requirements for long-term safety and effectiveness of data collection during the peri-approval and post-marketing periods pose both challenges and opportunities. The challenge is to design global studies to collect the right kind of data while providing cost-effective strategies and utilizing appropriate methodologies for analysis and reporting. The opportunity for providers of late phase services is to align with sponsors to develop service line offerings that meet the diverse scope of changing demands. This area of clinical research is one that necessitates the leverage of operational, regulatory and innovative technology.
DM: The gathering of Real World Data within the National Health Service of the United Kingdom results in "data obtained by any non-interventional methodology that describes what is happening in normal clinical practice". Such an ongoing exercise will not replace clinical trials. However, the data gathered in this way has the potential to (i) narrow the focus of clinical trials and (ii) to provide clinical information that can inform clinical trials. Furthermore, it should be possible to infer representativeness (or otherwise) of a clinical trial to the larger population and perhaps to identify groups within the larger population who stand to benefit the most from the results of the clinical trial.
LP: Cost Containment - Evidenced by the increase in outsourcing at fixed price contracts and the broader application of Standard of Care for the purpose of shifting procedure costs to 3rd party payers. Sponsors are negotiating terms with investigators in an effort to have them submit claims to private insurance and government programs to reimburse clinicians for procedures considered to be usual treatment for patients included in clinical trials.
2. How, in your mind, has the landscape of clinical trials shifted post-recession?
MW: While the United States and Europe are still the leaders of clinical research and innovation, trials are becoming increasingly global in nature. The Achilles heel of clinical research is finding enough qualified subjects to enroll in clinical trials. The areas with the most subjects that fit the criteria for clinical trials (drug naïve, willingness to participate, etc.) are more often found in developing countries of Asia (including China) and Central and South America. It’s the companies that can overcome the logistical challenge of conducting trials with subjects from all over the world that will prove most successful in the years to come. We’ve invested heavily in resources such as translation and cultural awareness to ensure BioClinica is ready to meet this need.
EM: North America continues to be The region with dictating power in clinical trials, and there is no sign of changes about that. Right now, Asia is receiving most of the attention (read money) of the clinical trial industry effort to expand to emerging regions, not only for its growth potential, but also for the expanding pharmaceutical market. Every single pharma company and big CRO wants to tackle China. However, the costs associated to bringing the industry up to speed fastly, and the cultural singularities of the region, require high investments. Some of the countries of Eastern Europe, like Poland, Czech Republic, etc have consolidated themselves as attractive markets, and with the added benefit of the proximity with big Western European markets in need to export their services and knowledge. Latin America is still a low-hanging fruit, where good results could be obtained with far less investment than in Asia. But the region still has to work hard to improve consistency of the regulatory processes, to be more competitive.
NA: The majority of originating work continues to come from the US and EU based pharmaceutical companies. However, we see a trend for originating work, particularly in the Biosimilar space, coming from Korea and Taiwan, and both biotechnology and pharma work originating from China. The latter are generally smaller studies intended for the local market. There is also a shift in participating regions and we see an increase in patients being placed in the BRIC countries of Brazil, Russia, India and China.
DM: In Africa there are well-trained scientific and clinical personnel capable of performing trials "in-house". Because of the large numbers of patients in Africa who as yet have not had the benefit of treatment, there are mutual benefits to performing clinical trials in Africa – benefits to the patients, benefits to those who run the clinical trials and benefits to the sponsor. Public-private partnerships offer resources otherwise unavailable to public and private organizations separately.
LP: Actually there are two regions, Asia/Pacific and Latin America. There are several reasons not the least of which is cost reduction. However, it is also driven by the need for naïve patients as well as an expanding interest of clinicians in those regions to participate in the development of innovative therapies and seeking incremental sources of revenue.
4. If things progress as they have the past five years, what can we expect in the next five years, with respect to clinical trials?
MW: This question reminds me of the investing disclaimer: "past performance is not a reliable indicator of future results." I expect we will do better than the last five years. As movement towards unified Clinical Development Platforms gains strength, I think you will see tremendous efficiency gains over the next five years, with the rate of improvement starting small and increasing every year over the time period. There will be less effort in the data management elements of running a trial, which will usher in a whole new era of collaboration in research. Of course, there will still be plenty of room for innovation. We’ve seen this in all manner of technology, the companies that embrace the standard and provide the best product will continue to thrive.
EM: I think the emerging regions will continue to grow in "market share" of sites and patients, and will continue to exhibit greater productivity and lower cost, but will not become dominant because the regulatory pressures in the developed world will demand a certain percentage of the data coming from their own backyard. Sponsors will progress in their quest for more streamlined protocols, which will be helped by the development of more efficient biomarkers. The big question is how much will we advance in the regulation of clinical trials. Will we accept the risk-based approach for the management and oversight of trials, or will we continue to progress in the trend to verify each bit of document related to the data?
NA: Following the publication in 2011 of consultation documents on Risk-Based Monitoring from the FDA and EMA, we anticipate a significant shift in approach to the management of clinical trials, so that proportionate measures are taken to mitigate the identified risks to patient safety and data integrity. ICON works with our clients to provide: a protocol risk assessment and monitoring plan designed for each trial; a focus on critical data and processes; appropriately reduced on-site monitoring and increased centralized monitoring, and use of real-time quality metrics to guide monitoring interventions. This approach is underpinned by intuitive data processing and analytical technologies.
Early stage clinical and biomarker development in the future will help to mitigate the high costs of Phase II-III failures. More extensive use of proof of concept research and the identification of appropriate biomarkers before moving to later stage research, will increase the demand for early, science based services. Using Adaptive Designs and with the help of biomarkers, the patient numbers involved in phase II-III studies may reduce over the long-term.
If the promise of personalized medicine is realized, the reduction in the size of studies may be compensated by a greater number of compounds being pursued. These studies will be conducted on a global basis and will require scale, depth of therapeutic experience and global network of services.
DM: With increasing interest in vaccines not only for prophylaxis but also for therapeutic purposes, there is likely to be more activity in the area of clinical trials for vaccines. The unmet medical need for prevention of serious infection, of maternal and newborn infection, of healthcare associated infection and of emerging infections means that vaccine trials will become more frequent.
LP: We can expect the increased use of technology to achieve the universal outcome: speed to study completion. We see the use of technology in protocol design, electronic data capture, site selection and patient recruitment. There is expanding use of technology in coverage analysis and identification of procedures (performance and frequency) considered standard of care. During the next 5 – 10 years there will be widespread use of virtual trial technology. But the most exciting technology both a technique and a therapeutic outcome will be in the application of the human genome.
5. What recent improvements/methods have been implemented to improve clinical trials?
MW: I believe there are many dozens of ideas that qualify for inclusion. But, the real change happens when these ideas become broadly adopted. One that qualifies is support for better decisions being made on a "real time" basis. Products like BioClinica’s Express EDC, for example, allow sponsors to better interact with their trial data and make informed decisions about the trial’s progression. They can easily see the results at any stage and determine if a process change is in order or even if the study should be terminated. In the past, this kind of information was practically inaccessible. It required months of data consolidation and was filled with errors. This will continue to get better as companies move to a unified clinical development platform. Another example is better utilization of the IT infrastructure to share and disseminate this information. Many legacy solutions ignored the desktop and trapped information in proprietary files or databases. Harnessing the information from desktops and leveraging existing investments in IT truly enable trial sponsors to do more, with greater efficiency.
NA: We believe that the intelligent use of technology has and will continue to bring greater efficiencies to clinical development and transform clinical trial processes. For instance, centralizing clinical and operational data through an information platform and showing trends visually will bring real benefits. We see enormous potential in being able to provide a single view of data from across a study or program that enables study teams to make more timely decisions on the course of a study. Real time access will also importantly improve safety by enabling medical staff to monitor trends more closely. Review of safety data will increasingly reflect modern medical practice where the electronic medical record has replaced the paper system; similarly electronic methods will be used to store clinical data for endpoint adjudication. Furthermore, as more trials use imaging as an endpoint, ce ntralized imaging, either as a repository or for a central read (or both), will become a "must-have".
Site performance data is also critical as a tool to enable increased enrolment effort, monitoring, training, or switch in sites. We believe that a critical factor in quality management is a focus on training and support of investigator sites, to improve consistency and reduce error at source. Accordingly, in 2011 ICON acquired Firecrest Clinical, a market leading provider of e-technology site support solutions, and has integrated these into our comprehensive technology portfolio.
EM: The most important ones are related to e-technologies, like e-data capture, e-regulatory dossiers, e-databases, etc. As an example, the development of technologies for capturing patient-related outcomes (e-PRO) has greatly improved the use of difficult to evaluate clinical measurements, like symptom scales. On the other hand, the expansion of the electronic medical records technologies has occurred largely in parallel with clinical study systems, and both areas are in great need of a convergence effort. The signal detection technologies for adverse event have also progressed significantly, but on the data capture and analysis side only. Investigators and ethics committees still struggle to analyse and make decisions on safety information coming out of clinical trials.
DM: Thought needs to be given to inclusion in a clinical trial. If, for example, patients for a paediatric clinical trial all become aware of the trial through social media, this may imply that (i) they are exclusive in having access to certain devices, (ii) they are electronically literate and (iii) those without devices and without electronic literacy don’t participate. Recruitment to a clinical trial should aim for representativeness and not exclusiveness.
LP: If we consider the sponsors’ top concerns to be cost containment while speed to study conclusion, many techniques to achieve these results are already being embraced. This includes expanded outsourcing at fixed price contracts, improved patient recruitment and site selection processes and the use of standard of care cost recovery applied beyond oncology studies to all therapeutic areas. CROs are leading the industry by working to reduce costs for their clients applying standard of care data to the protocols and recovering fees already paid to investigators.
6. Does social media have a place in clinical trials and why?
MW: Social media has filtered into just about every area these days and clinical trials are no exception. I mentioned earlier that subject recruitment is the Achilles heel of clinical research. Social media could be one of the most efficient methods of drawing a crowd of individuals with some kind of a unifying trait, interest, or inclination that may qualify someone for a trial. It might also help reduce drops outs by providing a support network for subjects who are enrolled in a trial. I think we’ve only scratched the surface of the possibilities that social media offers for clinical trials.
EM: I believe our lives have already been transformed by the social media, and it is certain that they are going to be important for clinical trials. The big question is how to start right, because information about a clinical study in a social medium can easily make it or kill it, with very little control by the sponsor or the investigator. Before deciding on the use of social media, we have to discuss how ready are we to deal with an empowered research subject.
LP: Social media technology is rapidly replacing the way we communicate, educate and incorporate our social needs within society. There may be a generational divide but as younger generations acknowledge these tools as acceptable and routine just as older generations accepted the telephone and television. This will lead to increased use in clinical trials in the area of recruitment and reporting with HIPPA compliance incorporated. Again all in line with achieving the major objectives of cost reduction and speed to completion of clinical trials with quality results.
Mark Weinstein
President & CEO
Bioclinica
Eduardo Motti, M.D.
Regional Head Clinical Operations Latin America
Pfizer Worldwide Research & Development
Dr. Nicholas Alp
VP & Therapeutic Area Leader for Cardiovascular
ICON Clinical Research
*Dr. E. David G. McIntosh
Global Scientific Affairs Sr. Expert
Novartis Vaccines and Diagnostics
* These views constitute those of the author and do not necessarily represent those of the Company Clinical Trials Roundtable for March/April Global Scientific Affairs Sr. Expert Novartis Vaccines and Diagnostics
Laurence G. Poli, Ph.D.
Vice President
TTC, LLC