Magazine Article | March 5, 2014

The Future Of Clinical Trials In An Outsourced Model

Source: Life Science Leader

By Rob Wright, Chief Editor, Life Science Leader
Follow Me On Twitter @RfwrightLSL

Throughout human history people have held a fascination with trying to predict the future, employing a variety of tools — crystal balls, palm readings, tarot cards, or my personal favorite, the Magic 8 Ball. Scientists typically use data when forecasting the future.

Another common future prediction tool, and one employed by Life Science Leader magazine for this roundtable, is that of expert opinion. I posed 10 questions to three clinical research experts to get a sense for the future of clinical trials in an outsourced model. The experts included Christopher Gallen, M.D., Ph.D., CEO SK Biopharmaceuticals; Mary Rose Keller, former VP of clinical operations, Sangart; and John Orloff, M.D., former SVP and chief medical officer, Novartis.

Of course, there are plenty of experts who have been wildly wrong when predicting the future, such as the head of Warner Brothers who said in 1927, “Who the hell wants to hear actors talk?” Conversely, there are examples of forward-thinking experts (e.g. Warren Buffett, Jeff Bezos) who have demonstrated a mastery of anticipating the future and capitalizing on it. Travel with me now as we journey into the potential future of clinical trials in an outsourced model.

Life Science Leader: How will future clinical trials (three to five years) in an outsourced model be different from today, and why?

C. Gallen, SK Biopharmaceuticals:
Replacement of thoughtless, copy-thelast protocol, high-variance designs by expanded use of genomic, biomarker, and clinical enrichment designs (e.g. randomized withdrawal) will produce a more informed population selection. Sophisticated modeling combined with smarter Phase 2 programs will better define the dose, design, populations, and desirable outcome variables to reduce false negative trials.

M. R. Keller, formerly of Sangart:
I don’t see a radical change, but I anticipate some evolution. CRO success is demonstrated in the metrics. CROs have the opportunity to influence study design and the elimination of excess secondary elements. Research from Tufts indicates sponsors are continuing to create complex protocols that are difficult to execute. CROs, as objective service providers, can help sponsors move toward more efficient and effective trial designs, and they will have the data to demonstrate the risks of poor trial design.

J. Orloff, formerly of Novartis:
There will be full operational as well as strategic integration of CRO resources with the sponsor’s global program team that will make the relationship less transactional and more cohesive. This model also will move beyond the execution of clinical trials to trial design and strategic input into clinical development plans, and it will require different skillsets and expertise on both sides compared to what commonly exists today.

What do you anticipate as being the biggest challenges in executing future clinical trials in an outsourced model, and why?

Gallen: Most trials and most CRO expertise is focused on the U.S. and Western Europe, while the vast majority of potential patients live outside that region. In the past, this made sense with the rationale of serving the big markets. But due to ecocomnomic and demographic changes, there will be a need to develop first-rate, costeffective trial-conduct capabilities in the Asia-Pacific region and potentially North African regions.

Keller: Colleagues who work within CROs are becoming increasingly disconnected from the discipline of drug development. Previously, it was common for many CRO employees to have sponsor experience, having joined a CRO when their sponsor company had downsized. Thus, they took their development experience into the new role. But now some CROs are staffing with individuals who have no pharma, biotech, or device experience. Inexperienced field staff may miss critical information due to their lack of knowledge regarding how medical practice differs from ideal drug development plans.

Orloff: The clinical trial enterprise is endangered because the model is antiquated and has not kept pace with advances in technology. Potential economic advantages of these improvements are absorbed by the legacy system. Incentives for an outsourced model must be reengineered to accommodate the need for more efficient practices in lower-cost settings, with rewards for efficiency and simplicity rather than volume and complexity.

How do you anticipate overcoming these challenges?

Gallen: I think that basic economics will prevail. On the demand side, pharma companies are beginning to appreciate that for drugs entering development now, much of their future market will be in the Asia-Pacific region. Biotechs are lagging in this knowledge both for reasons of parochial orientation and resource limitations, and because the specialty markets they typically focus on are more developed in the West. In any case, demand will increase. Some global pharma companies are developing a presence in the region, albeit at prohibitive costs. Competition from emerging local providers will drive pricing, while more opportunity will drive local and medium-to-large CROs to seize first-mover advantage. In parallel, I think most regulatory authorities will move toward ICH (International Conference on Harmonization)-type standards.

Keller: Project leaders need to have a plan to provide exceptional training and oversight to give monitors and managers the perspective required to achieve quality study execution. Sponsors must take staff “onboarding” seriously to ensure the CRO staff is well-versed in the goals of the project and endpoints of the studies. As we begin to more heavily rely on Big Data and remote monitoring, staff need to be able to critically review data for signals that impact the conduct and reporting for the study — again the ability to put everything into the perspective of the overall development process and plan.

Orloff: Fully integrated strategic partnerships between a CRO and a sponsor constructed to deliver on a program rather than á la carte transactional deliverables have the potential to reverse some of the existing incentives that undermine the goals of efficiency and simplicity. This could create a more cost-effective and flexible model that caters to the core skills of each partner.

In the future, what internal/external roadblocks will prevent companies from successfully executing a clinical trial in an outsourced model?

Gallen: Weak signals come from narrow, super-selective, mechanistically targeted compounds whose effects are partially neutralized by compensatory processes in complex systems. Pharma companies will develop more robust multimechanistic compounds using pathophysiological screening to increase signal strength and trial power. CROs focused on time and cost but not quality generate high variance results reducing power, requiring high intellectual expertise to use computer- assisted R&D to detect high variance sites and measurements and to correct errors and quality issues in real time before trials are compromised.

Keller: Misaligned goals represent a real roadblock seldom addressed by either sponsors or CROs. Although both organizations seek quality, sponsors are primarily concerned with time and CROs with cost, resulting in a difference in focus. “Us versus them” scenarios continue to be the norm. Communication between the internal/external parties is often limited to status reports to avoid difficult communication and issue resolution.

Orloff: Some roadblocks include competing incentives existing within traditional models, competing trials from different sponsors in the same disease area that impede enrollment, soaring costs in Western countries, increasing trial complexity, and lack of global harmonization in clinical and regulatory requirements, including study start-up procedures.

How would you approach minimizing the impact of these roadblocks on the successful execution of your trials?

Gallen: Regarding the internal roadblocks, the single most important consideration is strategic thoughtfulness. Specifically, there needs to be consideration of the right discovery approach to produce robust, differentiated compounds; the right selection of the initial indication most pertinent to and most likely to be responsive to a given pharmacological intervention into its pathophysiology; and use of the right trial design, power, and selection of dependent variables to detect and define the true effect of the medication on the disease. Essentially, you need to be smart about how you pick the drug to test, the disease to test it in, and the things to measure. The regulatory hurdles reflect political and sociological concerns as well as the career incentive systems of the regulators. Hence, you need to accept that these barriers exist, only undertake programs where those barriers will not be fatal to your chances of success, and work closely with the specific regulators to ameliorate the overall problem as it pertains to your therapy.

Keller: Every project must have a proper kickoff session to establish shared goals with clear roles and responsibilities agreed upon by sponsor and CRO. Frank, constructive conversations must occur between all the parties to establish the team, with members agreeing to honor the team objectives. Most start-up sessions focus on the tasks to execute, not how the team will work together. In addition, it is critical that both the sponsor and CRO agree to reward team members based on these shared objectives and goals.

Orloff: Each of the roadblocks identified above requires a specific focused approach, but for many of them, the challenges will not be completely overcome until we address the bigger issue relating to the business model for conducting clinical trials. In Western countries, conducting large-scale outcomes trials has become prohibitively expensive and inefficient. Novel approaches to the clinical trial model must be tested and explored, which include moving away from traditional clinical research settings at tertiary care centers to community-based locations that are closer to the patients we have approvtrouble engaging in the clinical research enterprise. Combining new communitybased models with disruptive technologies (eSourcing, eConsent, EMRs, Webbased approaches) has the potential to dramatically transform clinical research and put it back on a path to efficiency, success, and productivity.

What do you envision as being the biggest opportunities (e.g. social media) for conducting clinical trials of the future, and how should companies capitalize on these opportunities?

Gallen: At this time, the percent of the population with any given disease condition participating in a clinical trial is quite low — typically around a few percent. Social media, broadly speaking, is an important and underutilized means of educating and reaching potential trial participants.

Keller: I have become a fan of crowdsourcing. As the pharma industry moves toward greater transparency, it opens the door for greater input from the full spectrum of customers (investigators, researchers, patients, advocates). Many companies are posting a protocol synopsis for general comment from interested parties, and the results have been stunning in terms of improving the study. Also, new productive investigators have been found among those who are motivated to connect and comment.

Orloff: Web-based and social media approaches to identifying the right patients for clinical trials, especially in remote settings not currently accessed by traditional methods, would help to overcome recruitment woes. EMR (electronic medical record)-embedded electronic flags to providers are already being tested successfully in identifying potential trial candidates. Electronic consent is being used in some trials as a way to access new patients and facilitate their participation in clinical trials. Electronic sourcing will overcome the redundancies and inaccuracies involved in paper-based source documents, and it will enable realtime data monitoring to improve trial execution and ensure patient safety.

How do you think CROs of the future will differ from how they look today, and why?

Gallen: Frequently the large CROs are often undifferentiated (no distinguishing features) and inconsistent (great experience one trial, terrible experience the next). The reality is that CRO excellence does not vary as much at the company level as it does at the individual project team level. At Pharmacia and Wyeth, we found that by defining a superior system, training people on that system, and being rigorous in the training and selection of project managers (and culling those project managers who cannot perform at a high level), it is possible to create a dominant organization. Turf, habit, and the buddy system are the enemies of first-rate performance.

Keller: CROs are well-positioned to capitalize on information technology requiring increased standardization. I can see the CROs moving into direct access of patient data from electronic medical records and testing systems, as long as the data exists in a uniform format globally. The CRO systems will evolve to manage massive amounts of information in validated environments. CROs are more likely to develop this capability than individual pharma companies.

Orloff: CROs of the future will be operating in different business models compared to today (see above), becoming stronger strategic partners with sponsors. They will be fully integrated into team structures and will have accountability for delivering on a program with objectives and rewards similar to sponsor team members (i.e. much less transactional and much more strategic and program-oriented).

In your opinion, what are the key CRO attributes companies should be assessing today to successfully execute clinical trials of the future?

Gallen: Number one now and for the foreseeable future is the specific team of people who will be executing your trial. Number two is the sophistication of their systems and their ability to reduce the costs of subsequent trials by not duplicating the work done on the current trial (e.g. by using standard data management elements or formats). Number three is the ability to conduct trials in the regions most pertinent to commercially important approvals, not just now, but at the time your compound is improved.

Keller: CROs must be the early adopters of emerging technology, novel approaches, and new concepts, which represents an interesting parallel. In the same way many larger pharma/biotech companies have enhanced their portfolios by acquiring small, novel discovery companies, CROs will make similar advances and innovations by acquiring small specialty or niche CROs. Sponsors should look for demonstrated expertise in adaptive design, risk-based monitoring, and codevelopment of biomarkers/diagnostics and drug products.

Orloff: CROs will need to build their talent pipeline with the skillsets that support new operating models, with greater strategic and technical expertise, collaborative mindsets, and flexibility to work in diverse environments. And leadership will need to be open to alternative partnership arrangements that are tailored to the needs of their customers.

What tools and/or metrics have you found to be the best for effectively assessing these attributes, and why?

Gallen: There is no alternative to dealing with the issues in detail. Interview the pertinent CRO staff with detailed technical questions of how they recognize and deal with problems. Also assess nonverbal factors such as emotional intelligence and drive for results. Ask about rewards for retaining key staff and what punishments are in place for losing them. Of course, you should also look for industry-standard information systems.

Keller: Successful uses of the attributes I describe are relatively easy to assess through the data. For example, adaptive design requires quick turnaround of data and the ability to make seamless enrollment adjustments without a negative impact to timelines. True risk-based monitoring yields variable-monitor resource utilization and quality improvement, which are also visible in the metrics. It’s also important to assess the rate of acceptance of submissions to regulatory authorities. It is fine for a CRO to claim expertise, but it must be proven by achieving approvals.

Orloff: Many of the metrics for trial execution will remain the same (e.g. recruitment targets, enrollment by site, cost, data quality, etc.), while others will be more programmatic and strategic — metrics often used to assess an internal team’s performance, such as trial outcome (primary, secondary, exploratory), timelines, efficiency, patient safety, and adherence to GCP.

In your experience, what lessons have you witnessed being learned the hard way in executing clinical trials in an outsourced model, and what advice would you have on ways to avoid these hard lessons?

Gallen: First, various CROs are remarkably poor at costing out trials and preparing bids pertinent to your specific request. Bids for the same trial can vary dramatically between competing CROs due to a lack of understanding by the contracting people of what the RFP is actually asking. This can lead to selecting the wrong CRO based on the arbitrary nature of the bidding process. Another lesson I’ve witnessed includes selecting early indications based on the ultimate commercial target without actually determining the right dose and testing the hypothesis that the therapeutic actually affects the pathophysiology relevant to the disease. The key advice here is to define and review the proposal in detail, drilling down to understand real costs, and defining the development strategy in a manner that builds success into the process. One final lesson I’ve seen is being tricked by the “experience” of the CRO in conducting a given trial indication. It is only relevant if the experienced staff are on your team, not if they once worked for that CRO sometime in the past.

Keller: Projects change constantly. I see a distinct difference between internally resourced studies and outsourced studies in terms of how change is handled. Don’t freak out over the resulting change orders; focus on managing the impact of the changes on the team, the investigators, and the patients. Change management has to be in every project leader’s toolbox. Everyone knows that study amendments impact the cost and timelines, but if the quality of the study is maintained, you are still in business.

Orloff: Communication issues underlie many challenges that arise in an outsourced model. Lack of timely communication or failure to listen to legitimate requests from either party can seriously undermine the relationship and introduce unnecessary delays or even compromise the outcome of the trial. Integration of the outsourced personnel into a cohesive team model, along with good up-front strategic planning, will help to mitigate many of these issues. Leadership on both sides can help by fostering a collaborative team environment.