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TRIAL DESIGN : Enrollment is More Than a Numbers Game  REGULATORY : Late Phase PK Collection  Also in this issue : Protocol Design and Study Management, Effects of Europe?s Economic Turbulence, Ready for Big Data?, Outcomes Assessments

Applied Clinical Trials Digital Edition - February 2012

Clinical R&D organizations have placed increasing emphasis over the past decade on finding clinical research subjects in emerging global regions including Asia Pacific, Eastern Europe, and South America. This emphasis has multiple business drivers, but perhaps the most prominent is the ever-increasing competition for subjects.  

 Interestingly, enrollment metrics compiled from the Medidata Insights metrics warehouse—comprising close to 1,700 studies from 50 R&D organizations—tell a somewhat different story. The graph displays the relative proportion of trial subjects recruited annually from each of four global regions, from 2008 through 2011. In particular, the trend in proportion of subjects recruited from Eastern Europe and Asia Pacific appears to be flat or even slightly down over this four-year period, while the trends for North America and Western Europe are flat or even slightly up over the same period. 

North American enrollment rose slightly, while Asian Pacific slightly fell. 

It is not clear to what extent this trend will continue. What do you think the main drivers are? Can it primarily be attributed to the economic slowdown? Have sponsors concluded that conducting studies in these emerging markets is too complicated? Stay tuned as we will definitely keep an eye on this trend to see how it plays out in 2012.  

Each month, an Insights metric to highlight emerging trends in clinical development will be featured. For more on the industry benchmarks and clinical business analytics capabilities of Medidata Insights, please visit 

Unexpected Trend in Global Subject Enrollment

For years ISR has tracked the dynamics that surround patient and investigator recruitment. Not surprisingly, the industry has challenges associated with recruiting patients into many of its clinical trials. These difficulties aren't confined to just recruiting the patients. The industry has struggled—and continues to struggle—with predicting the recruitment of patients; the process known as feasibility in our industry. For years the industry has relied on poor quality databases, rudimentary questionnaires, and fading technologies to estimate trial recruitment. Even today 36% of the industry relies on fax-based questionnaires to prospective sites to generate recruitment estimates.  

But there is reason to be hopeful. In 2009, as part of its Patient and Investigator Recruitment Success research, ISR asked industry representatives how often they rely on various information sources, processes, and technologies as part of their feasibility and trial planning process. Only 14% of respondents indicated they used electronic medical records data to estimate recruitment and 49% indicated an intention to increase this use. It turns out their predictions were correct. In its 2012 update of this research ISR found that 21% of respondents are using EMR data for feasibility estimates. And just as important, 52% indicate that their use of EMR will continue to increase over the next three years.  

Increasing the Use of Technology in Feasibility

Outsourced safety services in the past were rather limited. Traditionally, pharmaceutical companies outsourced SAE/ADR management, pharmacoepidemiology studies, and individual consultancy. Concerns about confidentiality, data security, and liability in cases of regulatory non-compliance were—and still are—important factors against outsourcing. However, the increasing demand for pharmacovigilance capacity and expertise cannot always be satisfied in-house, whether constrained by limited resources, or a lack of appropriate infrastructure or regional presence. Consequently, the changing industrial and regulatory environment leads to re-evaluation of the advantages and disadvantages of outsourcing.  

The benefits of outsourcing in general also hold true for pharmacovigilance services. Fixed resource costs are converted into flexible workload-oriented costs. In the outsourcing model, pharmaceutical and biotech companies reduce costs because significantly less effort is needed for recruitment, management, and training of staff. Since safety concerns about marketed medicinal products resulted in stricter regulatory requirements, the job market for hiring experienced safety personnel has become highly competitive. The special benefits of outsourcing pharmacovigilance services include access to unique expertise, intellectual property, and multidisciplinary knowledge at the time they are actually needed. Because the contracted experts are external, they can provide an unbiased view. This impartiality can be of special value in a decision-making process. 

Nowadays, all of these tasks are outsourced. In addition, sponsor companies ask for specialized pharmacovigilance services, such as: pharmacovigilance audits to prepare for inspections; delegation of the role of a qualified person for pharmacovigilance; development of product information; and process design and SOP generation. With the growing demand of regulators for risk management programs, sponsors also seek support in the development of such programs. Although in general all tasks related to pharmacovigilance and risk management are outsourced, the needs of individual companies vary significantly. Company size, the size of the pharmacovigilance department and existing license or development partnerships influence the outsourcing decisions. 

Small biotech companies typically have no drug safety department and therefore have to outsource all routine safety services including the safety database. Only high level activities including analysis and decision making are kept in-house. Internal safety and risk management expertise as well as the resources to manage and control the vendor are many times limited. It is often this conflict between the sponsor's limited safety and risk management expertise; and being overzealous in the decision making process, which causes the most dissatisfaction for both parties. 

Mid-sized pharma companies generally have the knowledge and resources to cater to the demands of the global pharmacovigilance environment. Typically they require additional support to meet fluctuating resource needs associated with a changing product development pipeline. For example, support will be needed to cope with medium-term resource challenges, such as increased SAE volume due to a new clinical program. They also have limited geographic coverage and often require additional support in unrepresented countries. 

Large pharma companies have large pharmacovigilance departments with a global safety database as well as global infrastructure, knowledge, and expertise. Outsourcing occurs mainly for low-cost solutions and sometimes to support peak workloads. However, the areas of concern for low-cost off-shoring and outsourcing are quality issues and regulatory non-compliance. It is pertinent to maintain the necessary oversight and engagement with the outsourcing partners or the vendors. Stepping in early to mitigate or control an issue before it gets out of hand is something large companies need to be aware of and plan for. 

Pharmacovigilance activities which are outsourced vary significantly. The range of contracted services is reflected by the spectrum of safety service providers: individual consultants, specialty clinical research organizations (CROs), large "full-service" CROs, and global service providers under the umbrella of business process outsourcing. To achieve a successful cooperative relationship, it is crucial to select the best provider for the actual need. When considering outsourcing of medium to large-scale routine work, pharmaceutical companies should also take into account that shifting work to an external provider can free up internal resources for the increasing demands of quality control and/or for more intellectual tasks, such as signal detection and/or development of risk management plans early on. 

Considerations that affect provider selection: What services will be outsourced first? What are the future outsourcing plans? Is this the first in a series of contracts for similar or different services? Is this a one-time request for consultancy? How are various outsourced services linked to each other? 

Outsourcing pharmacovigilance activities is a standard business practice in a rapidly expanding market segment. Irrespective of the required type of support, the outcome will be a positive experience if the following rules are adhered to: the service provider has the qualification for the pharmacovigilance service; the contractual agreement includes well defined responsibilities; and communication as well as escalation paths are clearly defined at project start. Regardless of the level of sponsor involvement, consensus has to be established and maintained—cooperation in pharmacovigilance remains a collaborative effort. 

 PhD, is Vice President, Safety and Risk Management at PRA, e-mail: 

Sponsor/CRO Key to Business Relationships

The best relationships between sponsors and contractors are those that are well defined from the outset.

Pharmacovigilance Alliances

Clinical Research Associates (CRAs) at PPD receive standardized training so they can monitor trials the PPD way. Prior to June 2011, this geographically dispersed group of professionals would travel to the nearest PPD regional hub to undergo a 10-day course. In early 2010, Mike Wilkinson, Executive Vice President and Chief Information Officer of PPD, began looking for ways outside of traditional classroom training that would still produce the highest quality CRAs, but would also be more engaging to the CRAs, and maybe save travel costs in the end.  

Mike Wilkinson is Executive Vice President and CIO at PPD. 

What Wilkinson found was a 3D virtual collaboration environment from ProtonMedia called ProtoSphere, which allows individuals to engage and learn in highly social, interactive, and visually appealing three-dimensional virtual spaces. ProtonMedia promoted its technology across industries for collaborative meetings and events, but Wilkinson saw promise for virtual training. 

PPD's clinical staff and its professional trainers spent three months adapting the company's CRA training program, which had featured face-to-face training and PowerPoint, for the new virtual environment. The final product is now called PPD 3D.  

"It's very immersive," said Wilkinson of PPD 3D. "The CRAs create an avatar, which is a representation of you in the digital world. The CRA controls the avatar's movement from room to room and certain gestures like raising a hand to ask a question. The CRAs are looking at the screen, but they are immersed in what their avatar is doing." 

For example, during one training session, the CRA goes with the trainer to the doctor's office. In the traditional model, the instruction is given using PowerPoint, and then the trainer and a CRA would role play this interaction, with other classmates observing. With PPD 3D, the instruction takes place in the virtual world and each CRA enters a virtual doctor's office, opens the virtual door, walks through and greets the avatar receptionist, sitting at the virtual reception desk. CRAs then engage in virtual source document verification. 

Wilkinson explained that the CRAs don't feel as if they are looking at a computer screen but like they are in the actual room. In addition, the program allows more customizations that are globally sensitive and appealing: avatars appear culturally appropriate and are actually greeted in the way of that culture.  

"CRAs are required a day before to meet their tour guide in the virtual world for an hour so they understand what the process is and how to work in the environment," said Wilkinson. "We've learned to make that tour guide culturally specific and aligned, and that makes the CRA much more comfortable."  

Wilkinson said another benefit of this technology is the cost savings. He said that PPD was able to realize return on the initial software investment within six months by eliminating travel to hubs for face-to-face training. They have completed 11 courses so far and now hold two virtual trainings per month, with plans to do as many as they can virtually. There is also the possibility of doing a hybrid approach—part virtual, part in person. Formal assessments of post-training test scores show that virtual training is every bit as good as traditional training. Based on engagement and feedback, there is a clear preference for the virtual training. Said Wilkinson, "They are having more fun and they are more engaged. They also send us suggestions on ways to improve the virtual training, and we have incorporated many of them." 

Instead of traveling to a PPD training site, students of the new program learn in a virtual space. 

PPD is now working on initiatives to incorporate the technology for investigator meetings, team meetings, virtual visits to other offices, and more. For Wilkinson, the technology has brought together his former professional role with his present one. For three years, Wilkinson served as PPD's Global Head of Clinical Operations, and prior to that he was the Global Head of Internal Medicine at another company. Eighteen months ago, PPD offered Wilkinson the opportunity to be CIO in an innovative capacity, integrating information technology, global training, business analytics, and process improvement. Wilkinson said, "In operations, I was always looking for a better way to train our CRAs that was both engaging and cost-effective. And we delivered that in PPD 3D."  

Now, in his technology position, Wilkinson believes his past operations experience helps the company align PPD's technology and performance strategy with the overall business strategy. "It's helped IT understand the business better and helped the business appreciate what technology and performance improvement bring to the table." 

News

PPD has begun training its Clinical Research Associates in a virtual classroom.

PPD Trains CRAs in Three Dimensions

, PhD, have joined the not-for-profit research organization to lead two key departments within its Drug Development Division, a technology group that primarily provides contract preclinical drug development services for the pharmaceutical industry and government clients.

 to the position of Executive Director, Oncology Europe.

 (Philadelphia, PA) has appointed seven scientific and business leaders to its board of directors including 

, MD, Chairman of the ACR Image Metrix Board of Directors, Partner at Radiology Associates of North Texas; 

, MD, Chairman, Department of Radiology and Radiological Science at Johns Hopkins University and Radiologist-in-Chief at Johns Hopkins Hospital; and 

, MD, Chief Executive Officer at ACR Image Metrix and Executive Director of American College of Radiology. In addition, 

, MD, Former Vice President and CMO of Celera; 

, MD, Chair of the Department of Radiology at Emory University School of Medicine; and 

, MD, Chief Scientific Officer at ERT, have been appointed to the board of directors.

 PhD, Vice President of Worldwide Operations. Working out of invivodata's headquarters in Pittsburgh, Summa will be responsible for managing the successful implementation of invivodata's ePRO solutions in clinical trials around the world.  

(Morrisville, NC) announced the addition of 

as Executive Vice President of Clinical Operations, to its growing team of clinical development experts.  

, PhD, as the new Global Science Leader and Vice President for Biotechnology Services. Kaiser will replace Carl Martin, PhD. 

(King of Prussia, PA) President and CEO. He succeeds 

, MD, who has been elevated to Executive Chairman to the Board of Directors. In addition, 

 (King of Prussia, PA) has joined the company as Vice President, Global Business Development and 

, MD, has joined the company as Senior Vice President and General Manager for its newly formed Pharmaceutical Development Business Unit. 

has been appointed Vice President and General Manager, Europe, Middle East, and Africa.  

• With more than 18 years of experience, 

 (Exton, PA) as Executive Director, Biometrics, responsible for Biometrics Services.  

Bringing 23 years experience within the pharmaceutical and CRO industry, 

(Dublin, Ireland) as Group President, Clinical Research Services.  

 as Director of Business Development for the Europe, Middle East, and Africa region. 

 as the company's new Vice President and General Manager. 

 (Research Triangle Park, NC) has acquired 

, a privately held outcomes research firm headquartered in Cambridge, MA.  

, the CRO division of SRA International, Inc. based in Durham, NC, with offices in Paris, France and Milton Park, England. 

(Cary, NC) are working together to improve clinical development risk management and achieve targeted product profiles through analytics. They will offer biopharmaceutical customers an integrated suite of tools to increase decision-making speed, efficiency, and flexibility.  

(Buffalo, NY) announced the formation of a strategic alliance to develop a service portfolio tailored to the development of personalized medicines. 

 (Istanbul, Turkey) and together will cater to the Drug Safety requirements of Middle East, Europe, and West Asian countries. 

(Northwood, OH) has become the first organization to join 

(Minnetonka, MN) iMedNet CRO Partner Program. 

(Ingelheim am Rhein, Germany) has awarded 

 (Toronto, Canada) two projects with combined revenue of more than $18 million over a three-year period. The projects are both fixed-dose combination drugs in development for the treatment of the growing population of type II diabetics. 

 (Sawbridgeworth, UK) has received the European Outsourcing Awards held in Frankfurt. Exco InTouch has been honored with the accolade of "Best eBusiness/IT Strategy," which recognizes Exco InTouch's collaboration with Pfizer.  

Exco InTouch Wins Best eBusiness/IT Strategy Award at European Outsourcing Awards 2011 in Frankfurt, Germany. The company has been awarded the title "Best eBusiness/IT Strategy," which recognizes Exco InTouch’s collaboration with Pfizer. 

INTERLAB Central Lab Services—Worldwide

 (Munich, Germany) has been awarded with the Exportpreis Bayern 2011, the Bavarian Prize for Export Achievements in the Services Sector by the Bavarian Minister of Economy and Technology. 

 (Research Triangle Park, NC) has been named a winner in the 

 "Fast 50" awards for the third straight year. Given to the 50 fastest growing privately held companies in North Carolina's Triangle region, the award honors businesses for their contributions to the growth and success of the community. 

(Research Triangle Park, NC) has been named a finalist in 

annual Top 125, which ranks companies' excellence in employer-sponsored training and development programs. 

 has opened a new Central Laboratory in Bangalore, India.  

has announced the expansion of its Pharmaceutical Development services with the creation of a new facility at its UK headquarters in Craigavon. 

(Dublin, Ireland) resourcing division, DOCS, has expanded in Europe by opening four new offices in Milan, Italy; Budapest, Hungary; Brussels, Belgium; and Berlin, Germany.  

(New Providence, NJ) has launched Timaeus Guided Trial Builder, a new product that introduces a different approach to reduce the time and effort required to start up electronic trials.  

 (Craigavon, Northern Ireland) has released its new forecasting platform, COMPASS, which has been designed to improve the accuracy and efficiency of the supply inventory process during clinical studies. 

Business News

Industry news focusing on the people and organizations who work in the clinical trials profession.

Business and News Update February 2012

The turbulence buffeting Europe's economies is having multiple negative consequences—including in the pharmaceutical sector. Cash-strapped healthcare agencies are faced with ever-tighter public spending controls. Drug firms with significant presence in the eurozone are revising downwards their sales estimates and reconsidering their investment strategies. Uncertainty over the future is hitting long-term—and even shorter-term—planning in clinical development departments. 

Amid all the desperate macro-economic remedies being canvassed, there are some that contain nuggets of thinking that could, over time, prove beneficial to pharmaceuticals in Europe.  

The talk, in Brussels and beyond, is increasingly of a two-speed Europe—in other words, a rejigging of the 27-country European Union to create an inner core of more closely integrated countries with sound economies. Thus relegating less successful member states to an outer circle, a waiting room until they are ready to graduate to the elite class. 

Just who would qualify for the inner core is still an open question, and need not detain us long here. Certainly it will not be the same as the 17-member eurozone—Greece, Portugal, Spain, and Italy would clearly not be eligible in the near future. Certainly it will not be just the prosperous countries, because consistently successful Sweden does not even use the EU's single currency, and rich Norway is not even a member of the EU. Certainly it will not be just the big countries, because the UK is strongly opposed to the concept of closer links. But whatever its membership, the fuller integration it presupposes may contain the seeds of a solution to a dilemma that has made Europe a difficult arena for pharmaceuticals for half a century. 

An avant-garde of EU member states that pursue further and closer cooperation would have to decide how far that cooperation might go to ensure harmonious development. Already a new treaty is in the process of finalization among volunteer states that will bind them as never before on budgetary as well as monetary policy. There are other issues equally critical to closer economic alignment, such as taxation; labor market policy; and social policy, that have until now been jealously and ferociously guarded as the private preserve of individual member states.  

For the pharmaceutical sector, a shift towards alignment of health policy—also until now a matter reserved purely for autonomous national decision-making—could, if it occurred, mark the start of a revolution. It could mean the end of that still-unbridged gulf between the European and national dimensions of medicines policy that has bedeviled drug supply and development in Europe. No longer would distinct national pricing and reimbursement systems complicate product launch. No longer would national regulatory agencies insist on treating the same product in different ways. And no longer would multinational clinical trials have to fight their way through a jungle of conflicting national views. 

It's a big if. And there is no guarantee that a monolithic system across the inner-core countries would always choose to harmonize drug prices upward and burdensome regulation downward. But the seismic shifts that the economic crisis is generating in Europe are promoting a new open-minded approach to ideas that were, only recently, taboo. If member states are now prepared to accept the indignity of submitting their national budgets for prior approval at EU level every year—and that is what they are signing up to already—then some new coordination in health policy is no longer beyond the bounds of the imagination. 

While we are in the straws in the wind department (although on a less cosmic level), it is worth noting in passing that two major—but hitherto proudly separate—European industry associations in the healthcare area have just decided to join forces. EDMA, the European Diagnostic Manufacturers Association, and Eucomed, the European medical technology industry association, say their declared aim is to "ensure the place of in-vitro diagnostics and medical technology at the forefront of 21st century healthcare and healthcare policy." Working together will, they say, "enhance the effectiveness of the healthcare industry by providing our joint contribution to public health and research policies in Europe."  

One of the triggers for their decision is the evolving healthcare environment. They speak of "the need to further their close cooperation with regulators and policy makers on the upcoming revision of the legal framework for medical devices, which needs to be adapted to the specifics of new and emerging technologies." There they address accurately another strategic shift, as new science and new applications move remorselessly toward more personalized medicine, in which the previously watertight boundaries between industry sectors are progressively eroded.  

During 2011, some of Europe's pharmaceutical sector thinkers invested time and effort in exploring closer links between diagnostics and therapeutics  and admitted that they were not progressing at a rate compatible with emerging possibilities in healthcare. The same imperfect fit is evident between device and medicine manufacturers in the field of advanced therapeutic products too. Regulators in Europe nowadays repeatedly allude to the challenges posed by these cleavages. How long will it take before even more wide ranging mergers between industry associations occur? 

Back in the more immediate world of current affairs in strictly pharmaceutical affairs, it is impossible to ignore the fact that Europe is in a heightened state of expectation over the impending release of the proposal for an update of the clinical trials directive, which is still not out as of presstime. 

One of the chief preoccupations of the European Medicines Agency for 2012 will be implementing the EU's new pharmacovigilance legislation and balancing its introduction with budgetary and other resource constraints. From July 2012 it will start putting the plan into action. The new Pharmacovigilance Risk Assessment Committee will have its inaugural meeting in July, and the revised Coordination Group will start operating in September, at the same time that the agency begins to use the new urgent procedure and public hearings.  

It won't be simple. The agency will give priority to the elements in the legislation that contribute to public health. The next priority will be activities increasing transparency and improving communication. Only after that, if resources allow, will attention be given to simplification measures. 

As if that wasn't complex enough, the European Union is also aiming to introduce yet more pharmacovigilance legislation this year. The proposal, which tightens up drug monitoring rules, and, notably, prevents companies from discreetly withdrawing products without any clear explanation, was the sole focus of the EU Council's working group on pharmaceuticals, which met in Brussels in mid-January. The new elements are designed to plug the loopholes that were revealed as the Mediator safety case unfurled in France.  

Early last year, EU officials initiated stress-tests to see how far their newly-adopted drug-monitoring rules were capable of preventing another similar case. The tests showed gaps, which is why these additional proposals were quickly put together. In addition to requiring companies to explain any product withdrawal, these planned changes will provide for an automatic pharmacovigilance procedure. This will apply even to products that have not been authorized through the European Medicines Agency's centralized procedure.  

The automatic check is intended to come into effect "in the cases of specific serious safety issues with nationally authorized products, with a view to ensuring that the matter is assessed and addressed in all member states where the medicinal product is authorized." 

Look for an increasing shift towards electronic data use. A European survey claims wide support for using electronic health records for clinical research. One of the projects supported by the Innovative Medicines Initiative checked out opinions among researchers in academia; the pharmaceutical industry; system providers; and patients' organizations, and it reports that more than nine out of 10 respondents favor this approach. The goal of the project is to come up with a platform and business model to enable the re-use of data from such records for clinical research in Europe. Most of the responders to the survey highlighted the need to ensure that using electronic records is not going to fall foul of legislative, regulatory, ethical, and privacy requirements. But the impartiality of the results may be influenced by the nature of the project, whose title is a clear indication of its intention: Electronic Health Records for Clinical Trials. 

 is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium. 

View from Brussels

Europe's struggling economies may have unexpected effects on the pharmaceutical sector.

Looking Beyond the Euro Turmoil

Jean Paty, PhD, is the founder and chief quality officer of invivodata, inc., 2100 Wharton Street, Ste. 505, Pittsburgh, PA 15203, email: jean@invivodata.com, Web site: www.invivodata.com.

I cannot believe FDA did it again. For two years in a row, FDA comes out as the leader, pushing our industry forward. At the end of 2010, we thanked FDA for encouraging us to listen to the patient. This came through loud and clear in FDA's publication and promotion of their patient reported outcome (PRO) guidance at the end of 2009. PROs are direct reports from the patients that are not interpreted by a health professional. The propagation of PROs across product development programs, and the appearance of new PRO-based labels in the past two years is clear evidence we in the industry are hearing FDA's message. 

 In 2011, FDA went yet another step by telling us that there are multiple ways to give the patient a clear voice in clinical research. Specifically, FDA stated that we need to ensure all of our measurements and outcomes, not just PROs, reflect what is happening with the patient. In other words, we need to provide evidence that all of our instruments or tools measure what we think they measure. In FDA terminology, we must ensure that instruments or tools and their related outcome measures are fit for purpose in their context of use.  

Specifically, this means that instruments based upon a clinician's evaluation of a patient (ClinROs), and measures taken by an observer (ObsROs), like a mother reporting about her child, are subject to the same requirements for reliability and validity as PROs. FDA expects that all outcomes assessments (OAs)—ClinROs, ObsROs, and PROs—will meet 21CFR314.126(b)(6) requirements that "the methods of assessment of subjects' response are well-defined and reliable." The recommendations of how to meet the well-defined and reliable standard are delineated in the PRO guidance. In other words, FDA is using the PRO guidance as the yardstick by which it measures all OAs. 

The announcement regarding OAs came during an FDA-sponsored workshop held on October 19, 2011 at the FDA White Oak Campus in Silver Spring, MD. Both FDA and the industry were represented at this one day workshop. Janet Woodcock, MD, Director of the Center for Drug Evaluation and Research, gave the opening address and set the stage for OAs: 

 "Now clinical trial outcome assessments are one type of drug development tool that we have identified as ripe for improvement. The identification, development, and qualification of new clinical trial outcome assessments is an area that has really not been aggressively pursued by the scientific community, and the lack of—the consequent lack of assessment tools has been impeding, I think, the successful development of new drugs because we really in many cases don't know how to measure the impacts, both for good and ill, of the drugs that we test in people. And we can do better." 

This challenge from Woodcock also provides opportunity. OAs that are well-defined and reliable can support novel labels for our products, which in turn differentiate them from other treatments. There is now a defined regulatory pathway to novel product labeling. 

It is refreshing to see that regulators are prepared to help us in the industry meet the challenges of bringing new products to market, and most important, to create a pathway of success for these products. What do you have planned for 2012, FDA? 

, Senior Vice President, invivodata, Inc. 

A Closing Thought

All measurements and outcomes need to reflect what is happening with the patient.

Give the Patient a Clear Voice

Empty drug pipelines and ever-rising clinical research costs are prompting extensive soul-searching for ways to make clinical trials more productive and better able to support drug discovery and development. Everyone agrees on the need for more relevant studies, more efficient research methods, broader public support for clinical trials, a stronger pool of investigators, and more rational regulation and oversight of research activities. There's a healthy debate over how to get there. 

Food and Drug Administration officials promote a shift towards a quality-based approach to protocol design and study management, along with revisions in specific policies to support risk assessment. Leaders of the US biomedical research community contemplate more "transformative strategies" that integrate clinical research into the nation's healthcare system so it can tap electronic health records (EHRs). That would make it easier to identify patients suitable for clinical trials, record study data accurately and quickly, and document how new therapies can improve outcomes and reduce costs.  

Adoption of quality-by-design (QbD) and quality risk management methods for clinical trial management is the current mantra at FDA. This strategy was discussed by agency officials and research executives at a workshop in August 2011 organized by the Clinical Trials Transformation Initiative (CTTI), a partnership between FDA and the Duke University Medical Center that has gained strong support from industry and the biomedical research community; future CTTI workshops will further explore the QbD approach to clinical research. 

Anne Meeker-O'Connell, Associate Director of the Office of Scientific Investigations (OSI) in the Office of Compliance, Center for Drug Evaluation and Research (CDER), outlined the shortcomings of FDA's current oversight model for clinical trials, noting that lax internal controls by study sponsors often lead to significant data problems and systemic errors in applications. Inefficient practices, she noted, consume valuable resources and undermine research quality. Ken Getz of the Tufts Center for the Study of Drug Development emphasized the need to adopt a quality approach, starting with protocol design to reduce study complexity and thus curb the need for multiple amendments as the study progresses. 

The next step is for sponsors to develop an integrated quality management plan (IQMP) as part of protocol development. Under an OSI pilot, sponsors identify important risks and quality objectives to guide implementation of the clinical program. Metrics could include the number of subjects that fail to meet inclusion/exclusion criteria or a percentage of subjects with inadequate informed consent. Failure mode analysis can identify for sponsors what could go wrong and why, and how severely such problems would affect patient safety, data integrity, and protocol compliance. IQMPs may be particularly valuable for ensuring quality data from multi-regional clinical trials and for managing updates to research protocols in response to new information, problems with drug supplies, and unexpected events.  

A recent FDA proposal for reducing excessive and costly clinical trial monitoring illustrates the tenor of the risk-based quality approach. Sponsors feel they have to verify all data at every clinical site to avoid regulatory problems, Meeker-O'Connell acknowledged, even though FDA permits a variety of monitoring approaches based on risks to human subject protection and data integrity of a trial. To promote change, FDA published draft guidance in August 2011 that encourages sponsors to design monitoring plans based on key risk factors:  the complexity of study design and study population, investigator experience, data capture systems, and the relative safety of the investigational product. Sponsors should perform a risk assessment to identify what could go wrong with critical data processes, what would be the impact, and whether such problems could be detected readily, Meeker-O'Connell explained at the October 2011 FDA Inspections Summit sponsored by 

FDA also seeks to improve the quality and value of adverse event reporting from clinical trials, with an eye to reducing reports on less important, low-risk events in order to focus on more consequential safety issues. FDA issued revised regulations in September 2010 for safety reporting on experimental drugs, which clarifies responsibilities of investigators and sponsors for reporting serious, unexpected adverse events. CTTI is further assessing thresholds for reporting serious AEs and ways to relate safety reports to underlying disease to help sponsors implement the new rules.   

Internally, OSI is testing a risk-based model for planning its own clinical site inspections, initially for good clinical practice (GCP) inspections related to applications for new drugs and biologics; the plan is to extend this approach to oversight of institutional review boards (IRBs) and bioequivalence studies. This strategy also may be extended to OSI's collaboration with the European Medicines Agency on parallel/joint GCP  inspections. The regulators are sharing information on practices and schedules in order to improve methods, gain confidence in each other's programs, and conduct more joint and parallel inspections to reduce redundant oversight. 

A quality approach to clinical trial management also should be part of a more comprehensive transformation of the US clinical trials enterprise, according to members of the Institute of Medicine Forum on Drug Discovery, Development and Translation. The forum has been weighing options for such change for several years and wound up its deliberations at a November 2011 workshop on "Envisioning a Future Clinical Trials Enterprise for 2020"—a final report is expected this spring.  

The main conclusion of these experts is that clinical research needs to be linked more closely to the nation's healthcare system in order to attract sufficient financial support to facilitate the development of new, important medicines. Despite years of discussion, the envisioned "learning healthcare system has not really come together," commented Robert Califf of Duke University. Instead we have a process that "is slow, expensive, and often asks the wrong questions." Protocols are complex and burdensome, he said; over 90% of trials don't meet desired timelines, and many studies posted on 

 are small and inconsistently utilize randomization, blinding, and data monitoring committees.  

CDER Director Janet Woodcock noted that the demand for personalized therapies targeted to small patient populations illustrates the importance of integrating biomedical research into medical practice. Professional societies, payers, healthcare systems, and pharma companies all are important for establishing disease-based networks and supporting participation in and payment for clinical research;  FDA, in turn, needs to expand concepts for assuring quality data from trials.   

Amgen Senior Vice President Paul Eisenberg called for even more extensive reform of FDA's "onerous IND process," pointing out that the European Union's simpler notification system doesn't require a review of clinical trial materials and manufacturing processes at the research stage. US studies at multiple research institutions, he noted, are complicated by diverse contracting systems; variable informed consent and IRB  procedures; and difficulties in managing privacy requirements. Central IRBs would help, as would harmonization of clinical trial applications, nomenclature, and electronic systems for reporting and assessing adverse events. Bryan Luce, Senior Vice President at United BioSource, urged "real regulatory reform" that permits earlier, conditional approval of new therapies based on evolving evidence, acceptance of new methods and "trust across regulators, manufacturers, and payers."  

Health system executives highlighted how health system data systems can provide an infrastructure to support clinical research. Richard Platt of the Harvard Pilgrim Health Care Institute and Harvard Medical School described the use of EHRs to identify and enroll children in a study on reducing obesity and to support a massive randomized study on how hospitals can identify strategies for reducing antibiotic resistant infections.  

Another example is the Veterans Administration healthcare system, which has incorporated clinical studies into its healthcare program for years, according to Louis Fiore, head of the VA Cooperative Studies Program. Similarly, leading health plans around the country have joined the HMO Research Network, which now has some 20 sites at integrated healthcare systems that represent 10 million covered lives available for collaborative studies on vaccine safety, mental health, diabetes management, cancer, and other conditions. The aim is to conduct pragmatic, low-cost trials using EHRs to recruit, randomize, intervene and collect follow-up data, explained Karen Margolis of the HealthPartners Research Foundation. Centralized IRBs and template agreements on data sharing streamline operations, leading to strong patient retention, efficient adverse event surveillance, and ready dissemination of results.  

The discussion ended optimistically as Douglas Cropper, CEO of Genesis Health System, a community-based health group in Iowa and Illinois with little involvement in clinical research, expressed a high interest in using EHRs to support trials and outcomes studies. He encouraged researchers to get health system CEOs and clinicians more involved by appealing to their business and clinical interests in improving best practices and better managing chronic disease, and by embracing quality improvement methods.  

View from Washington

FDA wants sponsors to build quality into protocols, adopt risk-based strategies to streamline trials.

Quality Approaches Key to Transforming Research

Forging a sponsor/CRO relationship that will last—and that will benefit both parties—requires up-front planning, open communication, and feedback.   

Medpace's model for success has five key components, and these core elements have evolved over time and strengthened its partnership with sponsors.   

Define expectations regarding the quality of deliverables.

The sponsor and CRO should jointly identify key aspects of the relationship.  This should include the qualifications and minimal training requirements of the CRO personnel and the SOPs that will be used to run the study. It describes quality management plans and it defines the study plans, including the communication plan, the recruitment and retention plan, risk mitigation plans, and other strategic documents used to manage the program. It defines the expectations regarding audit readiness on the site and CRO level. 

Define the purpose of the alliance and outline the expectations for each committee involved in the governance relationship and key performance indicators and metrics that are going to be measured. 

Outline a multi-tiered oversight and management structure. There are often three levels of support:   

The program management team is usually made up of the project/clinical trial managers at the sponsor and CRO organizations. 

The oversight committee represents all the functional areas that may be involved in the project. 

The executive committee encompasses the VP/CEO-levels which shares strategic direction, pipelines, and prepares to move the alliance forward.  

Summarize the key milestones that have been achieved, upcoming deliverables, and the risks that are inherent in the program at that point in time. This is not a litany of the risks that have been observed throughout the course of the project, but those that are intractable or particularly critical, and they are ranked by the detail of their severity or urgency. 

Can include standardized quarterly reporting, task-based revenue accrual, and can give an indication of pass-through and escrow costs incurred versus what was budgeted up to that point in time, detailed invoicing history, and a listing of change in scopes as they have occurred by project and across the program. 

Key performance indicators should be defined so that the success of the collaborative team can be measured. As examples, consider:  

Measuring findings from process audits or CRO audits, and how quickly the issues are resolved. 

What kind of protocol deviations the sites are encountering? How frequent they are encountered? How they are being managed? How quickly sites are coming back into compliance. 

Clinical milestones to measure what was contracted versus what you actually achieved. 

Most important benefits for a sponsor when entering into a strategic partnership 

Minimizes the time and costs associated with identifying a CRO and negotiating the outsourcing contracting process.

Increases the visibility of the sponsor and the program within the CRO.

Streamlines communication and escalation pathways within both organizations.

Both organizations benefit from senior level medical, scientific, and operational oversight.

Other benefits include developing mutually agreeable processes and applying lessons learned from previous collaborations. Once a relationship is established, both organizations better understand the preferred method of handling certain situations and how the CRO can best operate within the sponsor's team structure. Lessons learned can be applied to other projects in the program which eliminates some of the inefficiencies that might be inherent each time a relationship is started with a new CRO. In conclusion, developing a strong sponsor/CRO relationship requires time, commitment, planning, and expertise. For this up-front investment, the rewards are many. 

PhD, is Senior Director of Clinical Operations at Medpace, 5375 Medpace Way, Cincinnati, OH.

Five key pieces to a lasting and successful sponsor/CRO relationship.

Strategic Partnership

Increasing regulatory scrutiny, greater patient and physician expectations around greater therapeutic effectiveness, and competition in the marketplace are putting pressure on pharmaceutical companies to develop new strategic plans for the transition from clinical research to commercialization, and for post-marketing research. It is the role of both the sponsor and their CRO partner to make the most of these critical steps.  

What new challenges and opportunities are biopharmaceutical companies facing as they move their products from clinical development into commercial marketing?

It's a much more consumer driven healthcare market than lets say 20 years ago. Government policy makers, public and private reimbursement agencies, healthcare providers, hospitals, even patients are much more focused on healthcare costs. Therefore, the pattern of consumption of biopharmaceutical products has changed significantly. These changes among industries' customers have had a huge impact on how they implement their research strategies and then their subsequent investment in the projects that they conduct. For example, 20 years ago it would be common that a small to mid-size pharmaceutical company may invest millions of dollars to bring another beta blocker to the market to treat hypertension even if that beta blocker was the 10th or 12th beta blocker on the market. Now, regulatory agencies and reimbursement groups are asking, why do we need that 12th beta blocker on the market? Unless there is a significant benefit in either the effectiveness or a decrease in adverse events; the product really is not worth reimbursing. 

What is the difference between late phase studies and clinical development trials? 

Two significant ones have influenced most clinical development strategies as well as operational plans. The first difference is the target audience. In clinical development trials, the key audience is the regulatory authorities. Sufficient data on the product's safety and efficacy need to be provided in order to pass that regulatory hurdle, therefore the design follows suit. For late phase studies, long-term effectiveness and safety is still a concern of the regulatory audiences, however, the policy makers, reimbursement authorities, healthcare providers, and patients are new audiences for late phase studies. These audiences are much more interested in the value of the product they are receiving. The second significant difference is the research objectives in operational plans of the two studies. Clinical development trials must operate by a very strictly defined research protocol of good clinical practices and international conference on harmonization guidelines. Late phase studies, with a less strict research protocol, are allowed to operate within a broader set of guidelines. A responsible CRO partner will ensure that late phase studies are still conducted using good pharmacoepidemiology practices and help sponsors through study design choices and tradeoffs. 

As stakeholders, what data do policy makers, reimbursement agencies, hospitals, and patients need to make their respective decisions?

The types of information will vary somewhat because these folks are making different decisions. Regulatory authorities will continue to focus on long-term effectiveness and safety. Reimbursement agencies, healthcare providers, and patients are interested in product characteristics that demonstrate the product's value. In other words, are patients getting the clinical outcomes that justify the cost of these new pharmaceutical products? Demonstrating value is often a key objective that is worked into late phase studies, in parallel with objectives of better defining long-term effectiveness and safety outcomes.  

As investigator participation is key to many late phase trials, how do you keep them engaged?

This is a huge challenge for sponsor companies. The FDA in the United States and other regulatory agencies are requiring more post-marketing or late phase studies on a growing number of pharmaceutical products. These requirements are placing a huge administrative burden on physicians' offices and their staff. Because late phase studies can operate within broader guidelines, there is a way to minimize the potential burden on sites, and should be part of the design considerations of late phase studies. Web platforms for example, make communications easy between the sponsor and the physicians who are participating. There are data collection technologies that can assist physicians with their administrative tasks relating to maintaining medical records at their facility. Most importantly—especially to the nursing staff who supports physicians—if the technology can provide data back to the physician with individualized reports on their patients, they can often incorporate that information into patient care plans. 

How important is technology in late phase studies? 

Technology is extremely important as far as supporting and enhancing the strategic value of late phase studies. Technology is constantly changing and how it's applied is constantly evolving. For example, with social media being used more and more to support late phase studies, whether that's developing a patient community around patients who have the common denominator of participating in a late phase study, or just providing information out to physicians. 

With considerable attention on global studies, how can sponsors prepare for marketing around the world?

The late phase area is strongly affected by healthcare policy laws, consequently the healthcare marketplace is constantly evolving. It is extremely important to have a presence in high growth regions, so that a sponsor can constantly monitor shifts in the healthcare delivery environment that may eventually impact the regulatory policies and reimbursement decisions related to their drug products. This will enable sponsors to be more proactive in their approaches rather than reactive to government decisions. As sponsors struggle to maintain regulatory compliance in different regions, it is critical that they have a partner with a deep understanding of the changes constantly occurring to help them proactively address those changes. 

is Global Head of Observational Research at PAREXEL International, e-mail: 

PAREXEL's Neal Mantick discusses the strategic advantage of the transition from clinical research to commercial.

Leveraging the Transition

spoke with Craig Lipset, Head, Clinical Innovation at Pfizer, about the current status of the REMOTE trial. Background articles on REMOTE and the participating vendors can be found in the August 2011 through November 2011 News sections. 

Craig Lipset is Head, Clinical Innovation at Pfizer. 

What is the status of the REMOTE trial and what has been the general response to date to the virtual trial model?

There is different data that we'll come out with over the course of the year sharing some of the status of the REMOTE trial in different settings. What I'll say right now is that we've had great support from our technology partners. We've had great support from regulators and ethics committees. We've had some challenges in terms of getting significant numbers of patients into the study. And that's okay because, in large part, if everything worked perfectly, then either we were geniuses or we didn't push the boundaries hard enough. 

While we may be smart, I think that we really wanted to make sure that we were pushing the boundaries here. And so we do view this as a learning project, where there are recruitment channels that we're exploring that are not delivering. We're capturing that data and reacting to it in real time and being able to make modifications in real time. 

So there's a great deal of learning that's been happening over the recent few months around recruitment channels. In particular, where recruitment is entirely online and looking to see which ones are able to deliver this particular patient population, which is a unique population. These are patients that have to be very highly engaged, perhaps more so beyond that of a typical patient. 

With your experiences to date, do you have any takeaways that you could provide for others looking to move toward a virtual model?

Make sure that the patients feel supported and that the process is as simple as possible.  

By feeling supported, recognizing that in this model patients are not having that in-person physical engagement that they're most comfortable with. And while many patients are comfortable doing a lot of transactions online, we have been educating consumers for years not to trust the Internet and not to trust sharing things over the Internet. And so we can't just step right in and say, "Well, don't trust anyone else, but you can trust us." 

So I think that we need to make sure that patients still feel a level of support. The intent with this model is not to say that there is no contact allowed with patients. The intent of the model is to make it more accessible and convenient. So phone conversations are completely fair to have. We have some experiments we're doing with visiting healthcare providers to the patients. I think as long as we're staying true to that goal of making the trial more accessible and convenient, we can do other things to make sure that the patient feels supported and well-engaged. 

Around simplicity, clinical trials are complex. Informed consent forms are complex. And so everything that we can do to help mitigate that complexity, help make sure that things are both readily comprehensible but also that the workflow is simple, I think that those are important, early takeaways. 

Pzizer's Craig Lipset answers questions about the ongoing REMOTE trial.

Early Lessons on Virtual Trials

I often wonder how people with jobs like me find time to read books anymore. By the time I've gotten through a day of meetings, e-mail, and business reading, there's not much time to absorb anything else other than a newspaper or a favorite periodical. My solution has been to listen to audio books during my early morning workouts. I usually confine myself to non-fiction business, science, and history books to help maintain a semblance of self-improvement, even though listening to a book does not quite achieve the same level of understanding as reading by eye. 

Once in a while, I pick up a book that is so compelling or complex that I find myself having to go back and purchase a print edition afterwards so I can read it the traditional way. This past holiday, such a book was "The Information: a History, a Theory, a Flood" by James Gleick. Gleick captivated me as he traced the history of communication, writing, messaging, cryptography and, ultimately, computing from ancient times through pioneers like Charles Babbage, Claude Shannon, and Alan Turing. It was surprising to me that the term "information" did not really exist prior to the middle of the 20th century—when people probably had the time to not only read real books, but also write letters and converse in leisure—and how critical information theory was in leading the way to computers, the Internet, and today's wireless computing world. 

As Gleick portrayed the transition from the spoken to written word, and from paper to bits, I found myself wondering how we're progressing as we handle information in the world of clinical research and development. 

One new trend to consider in this light is "big data," which refers to databases, measured in terabytes and above, that are too large and complex to be used effectively on conventional systems. Big data has attracted big vendors who have developed powerful new systems that combine massively parallel hardware and software to quickly process and retrieve information from such immense databases. In our world, big data solutions have been mostly employed to date in bench-research applications. In such cases, scientists have already gained experience in how to represent molecular, genomic, proteomic, and other complex, voluminous data types well enough so that they can benefit directly from the speed of processing and retrieval of big data appliances.  

But it seems that such systems would also be very useful for examining large observational healthcare databases of millions of patients to try to identify and explore safety signals. Yet it is extremely challenging to meaningfully merge and combine such data into a single research database, because the content, context, and structure of such data from different sources is so heterogeneous. Continual movement toward electronic healthcare records, together with advancements in standards and systems may get us closer eventually, but the path will likely continue to be long and tortuous. And the current business model of either tapping into a data provider's system one at a time, or downloading local copies of each data source, coupled with the risks of maintaining privacy and compliance compounds the problem.  

Projects like OMOP, Sentinel, and EU-ADR are raising interest in exploring healthcare data, and available data sources and tools are improving all the time. For example, the UK government has recently announced its intention to make available National Health Service data to the R&D community. Yet while projects like OMOP reflect cross-industry, cooperative efforts to better understand methods and develop open source tools, sponsors are still locked into creating their own local copy of a research database by contracting with individual data providers one at a time and building their own data repository.  

Vendors have developed systems for massive databases, but are we data ready?

Applied Clinical Trials-02-01-2012