A 76-page official report has just been published on the jumbo European Union clinical trials regulation conference that took place in London on October 3. It confirms—if only timidly—what many have been saying unofficially for ages. The EU rules on clinical trials don't work properly. 

Avid followers of the subject may recall that 

 own—somewhat shorter—report of the meeting appeared on the magazine's Web site within days of the October meeting, under the title "Clinical Trials Directive Hammered at EMEA Meeting in London" [

actmagazine.com/appliedclinicaltrials/article/articleDetail.jsp?id=463968&searchString=october%203

]. The joint sponsors of the meeting, the European Medicines Agency and the European Commission, have delivered a weightier but rather more optimistic account of what went on [

www.emea.europa.eu/pdfs/conferenceflyers/clinicaltrials/report.pdf

Their summary records general recognition among conference participants of the merits of the EU legislation—a common legal framework, a legal basis for compliance with good clinical practice, and improved protection of individuals through ethical approval procedures for clinical trials. "The conference generated a very useful dialogue," it concludes. 

It does acknowledge that "in some cases, problems have been encountered." But it suggests that much of the difficulty arises from what it sees as nothing more serious than "different interpretations and different implementation in the national legislation of the member states," and that "additional clarification, guidance, and harmonization" could provide a sufficient remedy. Only then does it note the feeling among conference participants that solutions to "some of the difficulties experienced" will nevertheless need legislative changes. 

"Any change to the legislation is likely to take some time," the report goes on, so it backs the meeting's support for an immediate start to work on issues that can be resolved without such a change—notably multinational clinical trials, safety reporting and monitoring, noncommercial sponsorships/trials, CTA dossier and process, and IMP-related issues. "Other areas that will require specific attention include increased transparency and availability of information on clinical trials, and the application of ethical principles and GCP standards in developing countries," it adds. 

Any hopes that this meeting would reduce rather than widen the scope for discussion have also been quickly dashed by the immediate follow-up. The organizers invited further comment for a limited period after the meeting—and they certainly got it! A further 27 pages of observations and suggestions from more than a dozen participants who felt they didn't quite get their point across during the meeting itself appear on the EMEA website [

www.emea.europa.eu/pdfs/conferenceflyers/clinicaltrials/postconfcomments.pdf

]. They include concerns from industry, regulators, and academia. Shayesteh Fuerst-Ladani of Kuros Biosurgery AG in Germany raises the frequent dilemma of companies that have incorporated EMEA advice into their trial design and then find national competent authorities questioning the design and requesting changes. "Would it be possible to have a link?" he asks plaintively, and not unreasonably, between EMEA scientific advice and the assessment of national authorities. 

Valiantly defending the noncommercial sector, Dr. David Baldwin of the European College of Neuropsychopharmacology urges a rethink of trial classification. "If studies are unlikely directly to change clinical practice, they should not be classified as clinical trials, and the onus should not be that studies are clinical trials until proved otherwise, but rather the other way round," he says. Instead, "what is needed is a new class of study—'a small clinical trial' with maybe under 100 participants, which could be dealt with as an experimental medicine protocol." Without this change, he argues, the EU rules "will strangle research innovation in Europe, to the great advantage of our competitors in other continents." 

The question of insurance again reared its head in this post-meeting discussion. Ólöf Yrr Atladóttir of the National Bioethics Committee of Iceland says that in her country: "We are experiencing an ambiguous and problematic situation concerning insurance for participants in clinical drug trials." She wants to know how far insurance requirements might be coordinated within the member states, perhaps with agreement on "some base line." Her anxieties are shared by Professor Janet Darbyshire of the UK Medical Research Council's Clinical Trials Unit. In her view, "putting in place suitable arrangements for insurance and indemnity in other European member states is both complex and costly and requirements vary." She said multinational noncommercial clinical trials in Europe would be greatly facilitated if the EU "were able to support the development of a harmonized approach that provided adequate protection to patients without undue financial burdens for sponsors." 

Uncertainties persist among national authorities on other areas too. Professor Gunnar Alvan of the Swedish Medical Products Agency asks whether it is not "time to clarify the procedure for clinical trials approvals" by defining and distinguishing more precisely the respective responsibilities of national competent authorities and the European Union. 

With characteristic bravura, Francis Crawley of the Good Clinical Practice Alliance–Europe and 

 Editorial Advisory Board member has posed two questions to the organizers: In light of the meeting, do they believe that the EU legislation "is a major contributor or detractor to public health in Europe," and whether it helps or hinders "making Europe competitive in the global market place of clinical trials?" He also slices through much of the debate with the suggestion that "all distinctions between commercial and noncommercial/academic clinical trials should be eliminated" from the legislation. "Sources and nature of funding are not good clinical practice considerations," he points out. 

And in a direct challenge to the tone of the official report, Professor Kathy Pritchard-Jones of the International Society of Paediatric Oncology says: "We were very concerned to see that the presentations from the representatives of the Clinical Trials Facilitation Group thought that the EU Clinical Trials Directive was basically sound and that only some 'fine-tuning' was necessary." 

An official pharmaceutical industry view—although provided for a different purpose—makes the same trenchant point. "The Clinical Trials Directive has failed to achieve its stated goal of 'simplifying and harmonising the administrative provisions governing clinical trials' as well as creating a simplified and competitive environment for clinical trials in the EU," according to a submission from the European Federation of Pharmaceutical Industries and Associations (EFPIA) to a broader and separate EU debate on the future of pharmaceuticals. "The main problem," says EFPIA, "is that member states have adopted different approaches in implementing the clinical trials directive, so the benefit of a single approach has been watered down." It calls for "more coordination," more "agreement on definitions" and fewer "country-specific requirements which go beyond the directive." In addition, says the industry association, more radical action will also be needed. This should take the form of a new and optional alternative procedure for multicenter trials to cater for applications, approvals, and supervision, and that would provide a single approval, "since there are some fundamental weaknesses of the clinical trials directive that cannot be remedied via further consensus building." 

The November meeting of the EU's pediatric committee took one small step toward greater clarity on where clinical trials will be required—and where they won't be—under the EU's new rules for stimulating the development of medicines for children. The principle of these new rules is that every application for authorization for a medicine has to be accompanied by a plan for pediatric trials: a pediatric investigation plan. 

The committee is acting to remove the obvious anomaly of requiring pediatric trials for medicines with no role in the treatment of children. It is recommending class waivers for conditions that do not affect children, including 17 symptomatic conditions relating to different types of cancer, neurodegenerative conditions, and other conditions that occur only in adults. 

The list, which will be regularly updated, refers to waivers only for the treatment of these conditions; it does not offer waivers for medicines used for their prevention or diagnosis. Companies are, however, also entitled to seek waivers for individual products. At its November meeting, the committee adopted a product-specific waiver for lasofoxifene tartrate, from Pfizer, in the area of bone diseases. This frees the applicant from the requirement to conduct trials to develop this medicinal product in the pediatric population. It is the fourth product-specific waiver issued since the system came into operation. The committee is also putting in place its procedures for the assessment of pediatric investigation plans—which will remain an obligation for most authorization applications—or of requests for waivers. See page 24 for more on this topic.  

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

Articles

View from Brussels

EMEA and EC admit to legislation difficulties, and many voice their ideas in an effort to make improvements.

It's Official: CT Directive Poses Problems

Adaptive is no longer the future—it's happening now. Companies such as Pfizer, Merck, Novartis, and Wyeth are going full steam ahead, not just doing designs, but implementing them. Several have appointed a VP-level person to drive the adoption of these methods. 

The FDA and EMEA are also much more receptive than they were a couple of years ago. FDA has appointed a senior person, Dr. Sue-Jane Wang, to lead the review of adaptive design submissions. Adaptive conferences and Web seminars are proliferating. Suddenly, every consultant or vendor to the biopharm industry is an adaptive expert. 

However, the picture is a shade different from what people had projected two years ago. Then, much of the focus was on adaptive Phase III trials as well as on seamless Phase II/III trials. Those are, indeed, being proposed, and some are under way. But the real action is in Phase II dose-finding trials and even in Phase I trials for safety. There are several reasons:  

The FDA's concern about the potential for bias is much less with these trials than with Phase III registration trials.

Adaptive trials are most helpful when you do not know enough at the beginning of a trial to design it with confidence. This is more likely to be true in Phases I and II than in Phase III.

Getting the dose right through well-designed Phase I and Phase II trials is the best way to maximize success in Phase III, which then leads to a higher rate of NDAs.

Do we know how to deal with the statistical issues? 

 The answer is an unequivocal "yes," as long as you work with experts in adaptive design methods. 

Can we "sell" adaptive to the regulators? 

 Our experience is that you can, as long as you can show that there is a really good reason for using an adaptive design and thoroughly evaluate several options, including a nonadaptive one, and then submit the details of your statistical work as part of your protocol submission. When it comes to Phase I and II adaptive trials, regulatory acceptance is much less of a hurdle than in Phase III studies. 

Are there safety issues to be considered? 

 Safety issues can never be dismissed, but it is worth noting that in most adaptive designs, the number of patients on doses that go to market is almost never reduced, and is often increased. That means that the amount of relevant safety information almost never diminishes. 

Will sponsors accept an independent decision-making body? 

 It is probably hard to accept that decisions with major economic consequences will be made by someone outside the sponsor company, but it may be necessary to do so to satisfy regulators that the possibility that the trial will be biased is minimized. The FDA's position on this is evolving, and it may accept a "Chinese Wall" approach in certain instances, where a statistician from some other part of the sponsor's organization sees the unblinded data and recommends what to do next. This is again less of an issue for Phase I and Phase II adaptive trials. 

Will site investigators and IRBs accept the design? 

 It's hard to generalize, but if you discuss this with them early and figure out what their concerns are, the answer is probably "yes." 

Will patient consent be easy to get if they know the trial is adaptive? 

 Yes. You just have to explain again why this will not hurt their interests and may help. There is a question, though, whether patients will wait to enroll in a trial knowing that they are more likely to get the right dose if they wait. 

Can we get the data needed for the adaptive decision in a timely manner? 

 That depends on two things. One, can the patient end point be observed reasonably quickly, and two, are there adequate EDC and data management systems in place so that data for the adaptive decision are available? If it takes a long time to observe the end point, then adaptive trials will only work if a validated surrogate end point is available. Phase II trials of modest size can be run without sophisticated EDC and data management, but that will add to the cost. For Phase III, EDC and first-class data management are essential. 

Is the adaptive change to a trial going to be easy to implement at all the sites? 

 That is a multifaceted question. One facet is: Can we drop doses easily? The answer is "yes," if you have centralized randomization. You just assign a probability of zero to the dose in the randomization system, and the dose is no longer allocated. Another facet is: Can we enrich subpopulations? The answer is "maybe," depending on whether the sites have the capacity to do this or not. Careful selection of the sites will be necessary. A third facet is: What will the investigator need to be paid if the number of patients to be recruited is indeterminate until the adaptive change is made? Again, there is no general answer. You will need to negotiate the solution and possibly see some of the economic savings from adaptive trials evaporate. When this happens, it is important to remind yourself that the primary motivation for doing adaptive trials is not to save money, but to heighten the chances of eventual market success and to get there faster. The economic value of that far outweighs any cost savings or increases. 

 Good question! Imagine that the trial design team says, "The number of patients will be between 500 and 750, with an expected value of 600." What number do you budget for? Practice will evolve here, and as experience is gained, statistical tools will be developed to guide budgeting. Quite likely, sponsors will need to maintain a central pool of funds into which savings from adaptive trials flow and from which monies go to adaptive trials that incur added cost beyond the original estimate. 

Can we manage the medical supply logistics? 

 The concern here is overages and stockouts. Overages have generally been considered unimportant, but managing supplies for an adaptive trial in the conventional manner could lead to overages of as much as 500%. At this time, the only way to keep the probability of a stockout low without having massive overages is to simulate the supply system ahead of time and use the simulations to optimize the system of manufacturing campaigns, inventories, re-order points, re-order quantities, and shipping methods. Good simulation tools are now available, but their ability to optimize is still low. 

In the future, it is likely that supply optimization tools will be developed, and this will be a boon to the industry's ability to systematically conduct complex adaptive trials with ease. It is also likely that some of the vendors who supply clinical trials will create technological innovations in manufacturing, packaging, and labeling.  

Always consider the adaptive alter-native, whether in Phase IV, III, II or I. 

In particular, use adaptive methods to get the dose right in Phase II trials.

Consider the more classical group sequential design in any Phase III trial.

Compare the costs of the adaptive and conventional alternatives, but also compare the probability of success.

If you choose to do adaptive, do a thorough analysis of the statistics and be clear about how the adaptive change is going to be made, and by whom.

Make this thorough analysis a part of your protocol submission to the FDA.

Do thorough planning. Get a cross-functional team together that includes representatives of medical supply, manufacturing, packaging and labeling, biostatistics, project management, and the therapeutic areas, and charge them with doing the planning together. Do not leave the logistical and project management issues as an afterthought. With adaptive designs, the design is not complete until you have figured out how to supply the trial.

In particular, simulate the trial ahead of time: accruals, randomization, response, and medical supply.

One thing is clear: If you're planning a clinical study without considering an adaptive design as one of your options, you are not getting good advice. It's  

not good enough anymore to talk about the difficulties as though they were reasons for not doing adaptive trials. It's time to figure out how to overcome those difficulties. It's time to move, to learn by doing. Those biopharmaceutical companies that do this right will be the winners because their return on investment in drug development will outstrip the industry. 

 PhD, is chief executive officer  at Cytel Inc, 675 Massachusetts Avenue, Cambridge, MA 02139, email: 

Guest Commentary

No longer a futuristic concept, adaptive clinical trials have become a reality that must be considered.

Lights, Camera, Adaption

The European Union's new guideline for first-in-man studies with high-risk products requires sponsors to make a more detailed risk assessment and risk estimation before trials begin. This task should be based on scientific knowledge and anticipated predictability of the nonclinical models, according to Dr. Thomas Sudhop, director of the division for scientific services at the German Federal Institute for Drugs and Medical Devices (BfArM) in Bonn. 

Jenny Mueller and Nermeen Varawalla discuss the issues facing first-in-man studies at the Applied Clinical TrialsEuropean Summit in Berlin, Germany. 

"In cases of concern, case-by-case decisions are necessary. This requires an open and scientific-based discussion by the sponsor in the documentation," he said at the 

 European Summit, held October 29–31 in Berlin. "Early scientific advice before clinical trial authorization (CTA) submission might be helpful." 

The guideline came into effect in September 2007. It was introduced in response to the TGN 1412 incident at London's Northwick Park Hospital, in which a CD-28 super-agonist antibody caused life-threatening adverse reactions in six subjects during March 2006. 

To avoid such disasters, sponsors must discuss the mode of action, the nature of the target, and/or the relevance of animal models for all first-in-human trials in their CTA application,  noted Sudhop. Details about structure-tissue distribution (including expression in/on cells of the human immune system), cell and disease specificity, regulation, level of expression, and the biological function of the human target and downstream effects are also crucial. 

Sponsors should compare the available animal species to humans, focusing on target, structural homology and distribution of the supposed target, signal transduction pathways, and nature of pharmacological effects. High species-specificity enhances the difficulty in the nonclinical evaluation of the risk to humans, but does not necessarily imply that there is always an increased risk in first-in-human trials. 

Among general clinical considerations are the route and rate of administration, number of subjects per dose increment, sequence and interval between dosing of subjects within the same cohort, dose escalation increments, transition to next dose cohort, stopping rules, and allocation of responsibilities for decisions on subject dosing and dose escalation. 

"First-in-human trials should take place in appropriate clinical facilities and should be conducted by trained investigators who have acquired the necessary expertise and experience in conducting early phase trials," concluded Sudhop. "Units should have immediate access to equipment and staff trained for dealing with emergency and life-threatening situations. Intensive care unit facilities should be located nearby." 

Ensuring the well-being of subjects is even tougher in sub-Saharan Africa, where safety reports may not reflect the actual safety profile and safety profiles from other ethnic populations may not be applicable. Furthermore, ethics committees only exist in around 20 of the region's 42 countries, said Jenny Mueller, clinical trials support manager at the Medical Research Council's Laboratories Unit in West Africa, in a special lecture at the Berlin congress. Where committees do exist, there are often long intervals between meetings; no appropriate legislation in place; their actions and decisions are not always implemented and monitored; and they may suffer from a lack of independence. 

About 175 trials in sub-Saharan Africa are registered with the International Standard Randomized Controlled Trials, suggesting the region is not popular with the pharmaceutical industry. Female  subjects are often particularly vulnerable because consent is not always an individual choice for women, they may not be able or willing to agree to contraception, and they may face coercion due to a lack of affordable medical care, said Mueller, who discussed similar issues in her October 

." Nurses often act on behalf of investigators, who do not always speak the local languages, and participants are not accustomed to questioning doctors. Data collection is difficult due to a frequent lack of source document availability and accurate information on concomitant medication, and because subjects often estimate birth dates have the same names. 

"Proper design of case report forms is crucial, as is involvement of the study team, capturing only data needed to answer research question, and user-friendly design," Mueller said. "Use of electronic data capture (EDC) devices can help."

Show Report

ACT Summit Highlights First-in-Man Trials

The new year begins on a note of optimism. A major breakthrough in stem cell research promises to open the door to new biomedical research opportunities. The drawn out Congressional debate over user-fee reauthorization and drug safety regulation is over, and most parties seem satisfied with the resulting compromises. The vaccine industry is experiencing a resurgence after years in the doldrums, with important new vaccines on the market and more under development. Unlike many previous years, the Food and Drug Administration had a confirmed commissioner for all of 2007 and relatively stable leadership as a result. 

Sponsors of new drugs and medical products will be busy in coming months as they face continued scrutiny of drug safety and other challenges: 

 The legislative wrangling is over, and now the lawyers are in charge of deciphering what members of Congress really intended for many complex and contentious portions of the FDA Amendments Act. The main thrust of FDAAA is to promote drug safety by imposing added requirements on sponsors and enhancing FDA's authority. FDA now can require labeling changes, expanded clinical trial registration and results disclosure, additional postmarket studies, and curbs on DTC advertising. Sponsors hope that these more stringent policies, plus the threat of fines on companies that fail to follow the rules, will restore public confidence in FDA's regulatory capabilities. 

As the implementation process begins, FDA officials and legal experts acknowledge considerable uncertainty about many FDAAA provisions. One question is how and when sponsors will have to file Risk Evaluation & Mitigation Strategies (REMS), especially for high-risk drugs already on the market. FDA has to clarify a process for tracking and enforcing compliance with Phase IV study commitments. And new requirements for registering a greatly expanded range of clinical trials and trial results present a substantial challenge for FDA and the National Library of Medicine. 

FDA deputy commissioner Janet Woodcock indicated that a REMS may not be required for all drugs, in discussing FDAAA at a Food and Drug Law Institute (FDLI) conference in November. The agency will use its REMS authority "judiciously," she commented, noting that too many restricted drug distribution programs could increase confusion, harm patients, and decrease access to the therapy. 

 While implementing new programs, FDA faces the challenge of demonstrating that it has not become overly gun shy about approving new drugs for market. New drug approvals were down last year, as well as the number of new molecular entities (NMEs) coming to market. FDA is issuing many "approvable" letters that frequently request additional clinical trials to further assess safety issues, and many approvals carry narrower indications. Black box warnings seem to be proliferating, as well as agency safety alerts and advisory committee reviews of safety issues for certain drugs and drug classes. 

FDAAA moves to address these concerns by revising the presubmission meeting process to support a more predictable drug development and review process. The aim is to discuss drug safety and reach agreement on postapproval studies and product labeling earlier in order to avoid delays and achieve more first-cycle reviews. 

 The Medicare Part D drug benefit has significantly increased government payments for drugs, intensifying public scrutiny of prices, especially for costly biotech treatments. High Medicare expenditures for anemia-fighting erythropoietin (EPO), for example, sparked Congressional investigations and led to a curb on Medicare reimbursement for the drug. 

Efforts to reduce the nation's prescription drug bill continue to fuel the campaign to grant the government authority to negotiate drug prices for Medicare Part D plans, to further limit drug advertising, to require more disclosure of manufacturer prices, and to speed access to more low-cost generic drugs. To achieve this last goal, Congress will continue to seek a pathway for FDA to approve follow-on biologics. The legislators decided to drop such a proposal from FDAAA, but generic makers have not let up efforts to resolve the issue, and projections of big cost savings from biosimilars are likely to keep the topic on the front burner in the coming year. 

Push for comparative effectiveness analysis.

 The process for determining appropriate drug prescribing and pricing stands to benefit from comparative effectiveness reviews of medical procedures and products. Better information on what medical treatments work best for certain patients could reduce excess drug utilization, avoid unnecessary or harmful procedures, and support a more efficient and less costly health care system. These possibilities are boosting support for a larger government role in assessing medical treatment effectiveness, while health plans and payers also are demanding more evidence that medical products are cost-effective as well as safe and efficacious. 

The challenge for pharma companies is to encourage analysis of how medicines compare to alternative medical and surgical procedures, and to avoid using comparative assessments to control costs or to deny coverage for innovative products. Even if a study indicates that a drug may be less effective for many patients, there should be room to prescribe that product for a smaller patient population that may benefit. 

 In order to bring new therapies to market more efficiently, FDA continues to work with industry to develop new methods for testing and assessing drug safety and efficacy. The agency's Critical Path Initiative (CPI) encourages public-private partnerships to develop new biomarkers, assess drug quality issues, and explore new approaches for ensuring product safety. An important project aims to improve methods for assessing liver toxicity in preclinical testing. FDA recently launched a collaboration with Duke University Medical Center to streamline clinical trial operations through electronic data standards, updating review board policies, and establishing accreditation programs for clinical investigators and research sites. 

 Some members of Congress and consumer advocates want to keep scientists with industry ties from serving on FDA advisory boards. FDAAA allows some conflict-of-interest waivers so that experts will be able to provide advice when needed. FDA has issued new policies to make COIs and waiver policies more transparent and is taking steps to meet Congressional requirements for reducing waivers overall. 

Concerns that drug manufacturers exercise too much control over FDA policies have emerged related to the role of the new Reagan-Udall Foundation, created by FDAAA to support innovation and enhance safety for FDA-regulated products. FDA met the deadline for naming a panel, headed by former FDA commissioner Mark McClellan, to oversee the new organization. But Rep. Rosa DeLauro (D-CT), who chairs the House Appropriations subcommittee in charge of FDA's budget, has objected that industry influence may lead the foundation to encourage development of more profitable, but not necessarily safer, products. 

DeLauro plans to hold hearings on Reagan-Udall and other COI issues while also directing how the agency spends its annual budget. Sponsors have joined with the biomedical research community and other parties to urge a significant boost in resources for FDA to deal with continually expanding responsibilities. A big increase in user fees may alleviate some of the shortfall for regulating new drugs, but delays in Congress approving 2008 appropriations bill for most federal agencies blocked FDA from being able to tap into these resources for several months. The budget squabble, moreover, casts doubt on prospects for any significant increase in FDA funding in the future. 

 is the Washington editor of Applied Clinical Trials, (301) 656-4634 

View from Washington

FDA and sponsors implement FDAAA as pressure builds to curb drug prices and tweak the R&D process.

Changes and Challenges in the Year Ahead

TrialStat's EDC Platform Adds Graphical Reporting Features and More

(Ottawa, Canada) announces enhancements to its Web-based ClinicalAnalytics 4.0 EDC solution including graphical reporting tools, automated post data entry validation, and optimized study management. 

Version 4.0's browser configurable aggregated study reporting now allows users to isolate, retrieve, and view complex data sets, as well as evaluate and compare data sources from multiple study sources within a project. Its integrated post data entry validation automatically validates the accuracy of data across multiple forms and subjects based on a study's configuration and associated data validation rules. And its study management includes improved user permission interfaces, form level permissions, and date time controls. 

eShowcase

eShowcase: ClinicalAnalytics Version 4.0 Enhanced

For more information on this topic, please read:

Mission Possible: Rebranding Clinical Research by Kenneth A. Getz, Emma Sergeant and James Kremidas

The Clinical Investigative Site Network by Lee S. Scheible, Donald R. Russell,Karen J. Brinkman

Spotting the New Managed Site Networks by Kenneth A. Getz

As the marketplace continues to rapidly change, demanding better access to more cutting edge therapies at lower costs, the pharmaceutical industry is being forced to find more efficient and cost-effective approaches in conducting clinical trials while facing increasing external factors. Rising drug development costs, a limited amount of research participants, increased competition for research participants among pharmaceutical sponsors, and an increasing turnover of new investigators complicate the drug discovery process.

  Additional requirements from regulators (including more diverse subject populations; longer, larger, and more complex clinical trials; exhaustive safety studies; and increased postmarketing safety surveillance) add to the overall study length and increase development costs. 

The use of enrollment optimization processes, such as enrollment forecast modeling and trial simulations and the use of clinical investigative networks versus the typical decentralized single site model, should be considered to help improve the current trial model. The addition of well-designed e-clinical processes such as EDC, eSource documents, Web casting, and others should also be considered to realize optimal trial quality and efficiency. 

The study protocol is the foundation of the clinical trial recruitment rate. New study protocol designs, such as those for adaptive trials (which is an increasing trend among pharmaceutical sponsors), can have an effect on subject recruitment. 

Nearly one third of all clinical trial timelines risk extensions based upon under recruitment or under enrollment. Under enrollment can jeopardize the registration of a drug, while over enrollment risks trial budget overruns. 

Protocols that have not undergone a feasibility analysis can be problematic once implemented. Sections of the protocol may be utilized from similar historic studies. This can result in poor recruitment if key changes are not made in relation to the new study outcomes in key areas of the protocol, such as inclusion and exclusion criteria. Other factors affecting recruitment may be study implementation issues at the site or sponsor-related issues. Additionally, poor patient compliance may result due to ambitious study requirements. What solutions are available to this perplexing dilemma? 

Clinical trial simulation and modeling tools are emerging in early phase work as a means to identify appropriate subjects and study targets, streamlining a compound's overall clinical study plan by focusing resources on clinical studies having a higher probability of success. Simulations can range from very large-scale mechanistic models that require significant resources to utilize and maintain, to a reusable platform that allows for complex and repeatable in-silica (computer-based) studies. The use of these tools can lead to larger success rates in later stage trials. 

The availability of historic trial data is another invaluable tool to develop a data-based projection. It is ideal to have the study projection developed prior to study timeline development. Recruitment activities and acceleration techniques are more effective and less costly when implemented during the initiation of the study rather than as a rescue effort well into the study recruitment period. Key historic data that is essential in forecasting a study projection includes the percentage of sites recruiting zero subjects. Historic metrics, such as the time necessary for sites to become regulatory ready, can occur over weeks or months and need to be considered in study recruitment forecasts. Finally, the rate with which research volunteers randomize into the study can vary depending on the study's inclusion and exclusion criteria, regions of the world involved, therapeutic area, and indication. 

A common mistake is to develop a straight-line projection that incorrectly assumes all sites are able to begin recruitment on day one of the clinical trial. Another important consideration in managing the clinical trial recruitment period is to consider timeline knowns including study seasonality, such as the period between Thanksgiving and the new year. In Europe, similar seasonal considerations would include the summer holiday season of July and August. Finally, disease incidence and prevalence, certain treatment settings (i.e., maintenance or adjuvant regimens), and pathophysiology effect recruitment and study duration. 

Figure 1 is an example of a projection taking into consideration these important factors. The team projection is a simple straight-line projection used in early forecasting of the study. 

Registration studies are increasingly becoming globalized for both increased access to subject populations as well as for economic considerations. Global regions affect the execution of clinical trial recruitment. The Asia-Pacific, Europe, Latin America, and the United States have their own recruitment enrollment performances. Key differences may include disease incidence and prevalence, specific country regulatory requirements, unique Ethical Review Board review periods, and specific investigator performance. There are recent trends of executing clinical trials in developing and emerging markets such as China, India, Latin America, and Russia. 

Historic site study execution is another invaluable tool in the acceleration of studies. In the field, there is often anecdotal and reputation-based evaluation of site performance. However, a more empirical method of measuring site performance at the therapeutic, compound, and study level is the use of invaluable tools to select high-performing sites as a means of accelerating not only the subject recruitment but complete study execution. Additionally, historic site study quality is a key factor in site selection. 

The methodology used in Figure 2 looks at the total number of subjects recruited at the clinical sites and the mean time between subject randomization at the sites. Using a clustering model, sites are compared to each other in the specific study. The ideal site would recruit a large number of subjects with low mean time between subjects being randomized. 

High performing sites are illustrated as Cluster 4 performers in Figure 2. Sites having a lower number of total subjects recruited and a longer mean time between patients fall into Cluster 3. Finally, Cluster 2 sites recruited the smaller number of total subjects with the longest mean time between subjects. Sites recruiting one or zero subjects are not represented in the figure. Historical data indicates sites will perform in the same cluster grouping 70% of the time. Selecting historically high performing sites along with new sites can provide a level of assurance in recruitment reliability and study execution. 

Another means to accelerate clinical trials is to increase the number of subjects that would consider participating in a clinical trial. While health fairs and disease awareness campaigns can provide a temporary boost to enrollment in targeted areas around clinical investigator sites, the issue remains: The number of people willing to volunteer for a trial is very low. 

The Center for Information and Study on Clinical Research Participation (CISCRP) is addressing these issues. CISCRP's recent "Everyday Hero" campaign seeks to address the low rate at which people volunteer for clinical research, as well as to educate the public and enhance its perception of clinical trial participation.

  By improving the public's perception of clinical trial volunteerism, there is significant potential for increasing the rate at which clinical trials enroll, thereby enhancing public health. 

The clinical network model has been around for more than 15 years; thus, the use of clinical networks is not a novel approach. But in recent years, the clinical network model has shifted from a primarily decentralized structure often lacking streamlined, consistent processes across the network to a more centralized structure governed by core standard operating procedures, enabling the network sites to function in a more consistent and efficient manner. 

The old network issue of slower, more complicated processes adding more costs has become an issue of the past. Network processes that were often labor intensive, paper driven, and not properly enforced with network quality assurance staff have all been resolved, as networks have implemented internal quality assurance departments to ensure network core procedures are followed, and implementation of e-clinical processes offer a better approach. 

Networks are groups of independent clinical sites managed operationally by a central administrative core group. The central administrative group will often include various departments, such as project management, regulatory, safety, pharmacy, information technology, data management, finance, legal, IRB, and quality assurance. Each of the central departments, as well as the network sites, are governed by a set of standard network operating procedures maintained and enforced by the central quality assurance group. These procedures help to ensure that the network sites function in a consistent, compliant, and efficient manner. 

From a scientific or medical perspective, networks usually consist of central disease state committees made up of regional research leaders or disease state experts representing their areas or regions of the network. The disease state committees are led or facilitated by a research advisor or chief medical officer. The central disease state committee conducts scientific reviews to ensure that the best trial designs are run at the right time and with the right regions or sites within the network for optimal trial efficiencies. The disease state committee is assisted by the central network administrative group, which provides historical subject population and network enrollment data so that the best decisions are made for optimal trial placement within the network. 

Networks will sometimes differ in some characteristics, such as size, disease state focus (single vs. multiple), community based vs. academic vs. hybrid, and most importantly in their level of centralization (partial vs. complete). Regardless of the characteristics, it is extremely important that the sponsor accurately characterize the network and thus fully understand their organizational structure, capacity, strengths, limitations, level of centralization, and clinical services offered. Several tools and standardized approaches have been successfully used and previously published to assist with properly characterizing clinical networks in a timely manner. 

Networks have always offered various centralized Site Management Organizational (SMO) services, such as site selection, trial placement, trial feasibility surveys, enrollment forecasting, budget and contract development, site reimbursement, and project management along with various clinical site services such as subject recruitment, ICD administration, data collection, safety reporting, and pharmacy and clinical laboratory services. Recently, however, networks have begun to offer various CRO services, such as full data management services and reporting, medical writing, statistical support, regulatory document services, and trial initiation and startup along with quality assurance site assessments and audit services both within and outside of their network. 

This expansion of clinical services allows for true, one-stop shopping and thus a more efficient and consistent clinical model. But in order to ensure proper compliance, all networks and services should be assessed prior to any service outsourcing for proper procedures, training, system validations, capacity, privacy compliance, and overall regulatory compliance dependent upon what services are offered. 

There are several key elements to look for when analyzing a clinical network. Some of the most important include central standard operating procedures to ensure consistent and efficient network processes that help guarantee proper trial oversight, subject safety, and quality. Central quality assurance is important in order to maintain and enforce the procedures throughout the network. Additional key elements include central data management services that allow for more consistent and efficient data collection and centralized monitoring. Central regulatory document services allow for more consistent and efficient document collection for multiple sites to initiate under one regulatory process vs. multiple site processes, which can be very time consuming and delay trial initiations. 

Several additional key network elements to look for when analyzing and selecting networks include central pharmacy services, which help to minimize study drug shipments to multiple single sites and study drug waste, since many single sites may never enroll a subject. 

The network model offers several efficiencies that benefit not only the sponsor but also the investigator and the subject. The centralized administrative departments take care of most operational tasks, including contract and budget negotiations, trial initiations, regulatory document collection, IRB submissions, central pharmacy, and site payments, and also allow the investigators and their site staff to focus on conducting the trial, enrolling and treating their subjects (which helps with enrollment), data collection, and overall quality. The subjects benefit since the investigators and site staff spend less time on administrative tasks and more on treating and assisting them. 

Smaller, more remote clinical sites, which may lack the proper staff to perform all of the administrative tasks, can be considered for clinical trial participation as part of the larger clinical network. This increased opportunity allows for more cutting edge therapies to be offered to more investigators and their subjects while minimizing lengthy trips and costly travel expenses for subjects. In addition, the centralized or partially centralized network model allows for large efficiency and consistency gains since one regulatory document and IRB submission process is conducted to initiate multiple network sites. 

Central pharmacy services allow for one central drug shipment and less study drug waste. Central contracts and budgets allow for one budget and contract negotiation and development for multiple sites. Additional efficiency gains have been documented with central data management, allowing for centralized monitoring and more consistent data collection, as well as others which have been discussed in recent clinical network publications.

E-clinical processes are important because they maximize trial process efficiencies while also ensuring enrollment optimization processes, and network model efficiencies are optimized, as documented in recent e-clinical publications.

  These processes include virtual training (i.e., Web cast, Web sites, CD, DVD, Web conferences), which offer different options for training the clinical network sites and staff in a thorough, cost-effective, and timely manner. 

Document repositories (secure Web sites) are used for secure document delivery and enhanced communication among the network disease state and central administrative committees and at the satellite sites depending on the document type. The enhanced communication can help ensure that proper trial oversight and patient safety occur in the network trials. Secure email systems are helpful for rapid communication among the network and sponsor staff, while e-source documents and EDC systems can have a positive  impact on trials by allowing for centralized monitoring and more rapid data access, review, and query resolution. 

All of these e-clinical systems and processes also help to ensure that all of the network sites function in a consistent manner and that their records are maintained in a similar fashion. A key element is having a centralized network IT staff that will help to ensure that end-user functionality requirements are met, that system support services are offered, and that the systems are always regulatory compliant. Technical and help desk support and contingency plan development for prompt system and user issue resolution, often referred to as ancillary services, are also crucial for system and process acceptance and success. 

Feature Article

Steady enrollment and optimal trial metrics can become reality with the right processes and tools.

An Improved Trial Model

Views about racial disparities have changed in recent years. It is no longer the consensus that minority groups are less likely to participate in clinical research than nonHispanic whites due to historical abuses or even societal prejudices in general. 

New data suggests that under-representation of minority volunteers in clinical trials has a lot to do with the race and ethnicity of the clinical research investigator. This is one of the major findings of a study that my colleague, Laura Faden, and I recently completed. The Tufts Center for the Study of Drug Development (Tufts CSDD) study found that minority physicians participate in clinical research far less often than their white counterparts—most notably in FDA-regulated clinical trials funded by industry. Whereas 9.3% of all white physicians actively participate as principal investigators in industry-funded clinical trials, only 3.7% of minority physicians do. 

Although minority physicians are no less interested in participating in clinical research than white physicians, minority investigators tend to conduct and initiate only about half the number of trials annually as their white counterparts. They're also younger and have a more limited clinical research infrastructure. 

"The discrepancy between government- and industry-funded trials should come as no surprise," said Priscilla Igho-Pemu, MD, MS, director of clinical trials in the Clinical Research Center at Atlanta's Morehouse School of Medicine. "Only trials funded by the National Institutes of Health (NIH) are required to involve minorities. If not, you need a strong scientific rationale to not include them...not just that it's inconvenient or they're slow to recruit or noncompliant." 

Since the mandate went into effect in 1993, the NIH has "constantly refined inclusion requirements [and] monitored and publicly reported progress toward more balanced representation," commented Alfonso Alanis, MD, chairman and chief executive officer of Anaclim, an Indianapolis, IN-based clinical research organization that specializes in minority participation. The regulations, he believes, drove a lot of positive change in NIH-funded clinical research. 

"Minorities are woefully underrepresented even in studies of diseases, like diabetes, that disproportionately affect them," explained Alanis. To not have proper representation of impacted populations creates issues of scientific integrity and relevance. "There is now ample evidence that different racial and ethnic groups can respond differently to the same treatments. Given the significant growth of minority populations in the U.S., exclusion is also hard to justify from a social justice perspective," he said. According to the U.S. Census Bureau, by the year 2050, more than half of the U.S. population will be comprised of minority communities, up from 37% in 2004. 

The commonly held belief that under-representation of minority volunteers in clinical trials is due to the legacy of Tuskegee and distrust of the research establishment was challenged by a December 2005 

 article, conducted by David Wendler, PhD, and his colleagues. "We found that minorities are at least as willing to participate in clinical research studies as long as they are eligible, know about it, and are invited to volunteer," said Wendler, director of the unit on vulnerable populations in the department of bioethics at the NIH. Wendler believes the largest barrier to minority participation is access. "A lot of studies are conducted largely by white investigators in inaccessible places to many minorities," said Wendler. There are also a host of socioeconomic barriers, including the inability to take time off from work or to afford the transportation costs. 

"In inner city Baltimore, it has been relatively easy to attract male African-Americans to participate in research at the National Institute of Drug Abuse simply because that's their home turf," Wendler said. 

"It's still often true that people get in a trial as the result of a referral from their primary care and specialty care doctor. But minority physicians in the best position to refer would-be minority participants may not have colleagues from medical school running clinical trials. They may not even be able to spare the time to make a referral," said Wendler. "And minorities in lower socioeconomic groups have disproportionately more co-morbidities that can make meeting a study's exclusion criteria an obstacle. But access and knowledge about trials are the greatest hindrances overall," he said. 

"We recommend that [sponsors] open up sites in minority communities and involve minority clinicians and investigators," said Wendler. "In a lot of cases, it's relatively easy to do. This isn't an intractable problem." 

Morehouse's Clinical Research Center has successfully tackled some of the root causes of racial disparities: minority physicians are less likely to be trained in the clinical trial process, lack sufficient resources and contacts to identify trials, and have limited capacity to respond quickly when they're offered clinical trials. In 2002, the Clinical Research Center created the Community Physician Network (CPN) to overcome these hurdles while increasing the quality of care minority patients receive, says Igho-Pemu. Over 165 practices, more than half primary care, are in the network. CPN provides training and mentoring to practices interested in participating in trials. 

To enable CPN practices to more rapidly identify potential trial participants, four disease-specific registries—for hypertension, diabetes, metabolic syndrome, and heart failure—were created. "These registries provide a good cross-sectional view of what goes on in a practice and serve as a resource for evaluating clinical trial feasibility," said Igho-Pemu. She added that the "longitudinal" view provided by an electronic medical record (EMR) is an even better method for identifying potential participants, but is cost prohibitive for most solo and small-group practices at this time. 

"Due to heath literacy issues, recruitment of minority patients happens best via face-to-face at health fairs rather than newspaper advertisements," said Igho-Pemu. In the past year, the Clinical Research Center has participated in 24 health fairs, screened 2304 people, and enrolled 708 volunteers into studies. More than 1400 volunteers in its active participant database are waiting for suitable studies. 

To help practices set up the needed administrative structure for trials, CPN has three study coordinators available to help train sites' own coordinators. For the first time in March, it enlisted a professional research consultant to provide two days of Good Clinical Practice training to principal investigators and their study coordinators. CPN is now soliciting entry-level trials from industry sponsors for the 150 attendees, with the availability of a central IRB to expedite the approval process. It also seeks to establish master agreements with industry sponsors to eliminate contract uncertainties for fledgling investigators. 

For the past three years, Anaclim has been actively recruiting minority populations using one seemingly simple strategy: inviting minority physicians and practices with high volumes of minority patients to participate as investigational sites. The CRO maintains a database of 4000 minority physicians, about 400 of which have been utilized to date for 17 clinical trials. 

"We guarantee to provide patient populations that mirror the epidemiology of the disease we're asked to study," says Alanis. "Half of the time, we're hired by sponsors to do just the minority piece of a clinical trial." 

According to Alanis, minority principal investigators tapped by Anaclim are eager to participate in clinical trials. "They work hard and the quality of their work is very good. Their patients, who are often of the same race and ethnicity, put a great deal of trust in them. Hispanic and African-American physicians, in particular, tend to return to their home community to practice after medical school. Their patients are relatively easy to recruit into clinical trials, though they typically ask more questions about trial design and safety precautions because they want to be reassured that nothing bad is going to happen to them," said Alanis. 

Alanis has found that minority patients, existing disproportionately in lower socioeconomic stratums, tend to have special transportation, childcare, and communication needs that must be addressed if they are to be recruited and retained in studies. "Without some sort of compensation for missed time from work, many patients simply can't afford to make the study visits," he added. 

Pharmaceutical and biotechnology companies, the primary funding sources for trials of new medical interventions, have become far more aware of the need to address racial and ethnic differences in their clinical studies. This will require research sponsors to broaden their focus beyond performance and outcomes, accept the higher cost associated with minority patient inclusion, and willingly go the extra mile to identify minority investigators. 

The National Medical Association, which represents African-American physicians, is hopeful that pressure from prescribing minority physicians will help spur change. The organization has instructed members to ask drug company sales representatives to provide clinical trial data specific to African-American subjects if available. 

On a broad scale, new health policies are needed. At the Baylor College of Medicine in Houston, Armin Weinberg, PhD, is heading up the four-year EDICT (Eliminating Disparities in Clinical Trials) project aimed at identifying feasible policy strategies and creating synergy between groups that have independently discovered promising solutions. 

EDICT, initially sponsored by a grant from Genentech to Baylor and the Intercultural Cancer Council (ICC), "brings together stakeholders representing the public, private, and nonprofit sectors and focuses on erasing disparities in the areas of oncology and asthma trials," said Weinberg, director of the Chronic Disease Prevention and Control Research Center. "Nonprofits fund a fair amount of research but, like industry, aren't required to include representative samples of subpopulations." 

Weinberg added that EDICT has identified nine areas of opportunity for impacting health policy, including expanding publication review procedures to cover inclusion efforts, providing insurance coverage for trial participants, and improving the conversation between physicians and patients about the clinical trial option. "The recommendations will be launched at an ICC symposium in April 2008 before being disseminated nationally," said Weinberg. 

Two spin-off projects have emerged from EDICT, including application of National Standards on Culturally and Linguistically Appropriate Services to the clinical trials process. Team members are also nominating best practices and policies to include in a "backpack" of tools for eliminating disparities. A separate arm of EDICT is field-testing educational and support interventions for increasing clinical trial enrollment in underrepresented patient groups. These demonstration projects will result in a "toolkit" that can be easily modified to target any underrepresented population. 

Meaningful progress in eliminating racial disparities may require some degree of encouragement and/or enforcement by the U.S. FDA. "At the very least, the agency needs to start enforcing existing regulations that require new drug applications to report the ethnicity of patients in trials," said Alanis. "My hope is that pharmaceutical and biotech companies soon come to realize that the inclusion of minorities is not only the right thing to do, but provides a competitive advantage." 

For a copy of the results of the recent Tufts CSDD report quantifying minority disparities among clinical investigators, contact me or Peg Hewitt at 

MBA, is a Senior Research Fellow at the Tufts CSDD and Chairman of CISCRP, both in Boston, MA, email: 

Clinical Trial Insights

Lack of minority clinical investigators behind dearth of minority subjects in trials.

Tackling Racial Disparities in Research

To hear sponsors tell it, the complex business of conducting clinical trials is fraught with challenges, perhaps none bigger than the slowdown caused by underperforming investigative sites. From the site's perspective, clinical trials are characterized by demanding protocols, tough deadlines, grant payment problems, and enrollment pressures—difficulties all caused by the sponsor. Each side has been pointing the finger at the other for a long time. But now, with so much at stake, namely patent expirations, intense global competition, and heightened emphasis on safety, there is keen interest in making things better, in listening and learning from each other—essentially building a relationship. 

Some sponsors are becoming intentional in their efforts to build relationships with sites, hoping to turn more of them into predictably high performers. They are reaching out to sites to identify the issues they have with sponsors that create stumbling blocks and stall performance (see Table 1). The current thinking is that addressing these issues has tremendous potential for improving outcomes.

  A number of forward-thinking sponsors are investing resources to identify the issues and then retooling and implementing processes to make substantive and measurable changes needed to make site performance more predictable. 

 Table 1: Some key issues that sites have with sponsors. 

The subject of improving sponsor–site relations as a way to improve performance has been a topic of discussion since the late 1990s. At that time, articles and surveys highlighting the frustrations of investigative sites and their opinions of various sponsors started appearing in the literature.

  What is different this time is that sponsors are responding by making strong commitments of time and manpower in a way they have not done before. 

This article explores that commitment to intentional relationship building, sometimes known as investigator relationship management (IRM) or site relationship management (SRM)—all buzz phrases in the clinical trials industry referring to focused efforts by sponsors to intentionally improve relationships with sites for mutual benefit. Sponsors are moving ahead with these initiatives because inadequate site performance continues to be a major drain on industry resources, despite growing use of electronic solutions. 

There are data to suggest that 26% of sites recruit 80% of patients, and on average, 14% to 19% of investigators enroll one subject or no subjects.

  Much of this unsettling picture is attributed to insufficient infrastructure at the site, untrained staff linked to rampant turnover of study coordinators, and the high dropout rate of investigators after having completed a handful of clinical trials.

  This business model is not sustainable in today's highly pressured environment, so changes are in order. 

Throughout the past few decades, industry has paid a lot of attention to improving relationships among business partners. They emphasize adopting a customer-centric business model

  along with tactics that enable work groups to improve output, such as clearly defining roles, streamlining internal and external processes, and improving communication among team members. This common sense approach is most effective when it strikes a healthy balance between the cold, hard effort needed to complete a task and the softer people skills necessary to forge a committed relationship in an engaging, quality-driven working environment. 

Ruth Dubinsky, principal of Clarity Consulting (Ambler, PA), a team building organization, says that sponsors and sites are happier and do better work when they intentionally form relationships. "When all people do is focus on the task that needs to get done, and they take out the human element, so much is lost and people are less productive, yet that's what people do. When people are relegated to just being taskmasters, and the human element gets stripped away, everything is very robotic, often leading to continual problems with turnover, lack of commitment, and less quality," Dubinsky says. 

To re-introduce the human element and essentially upgrade the relationship between sponsors and sites, a number of sponsors are engaging in initiatives to figure out exactly what sites want in the way of a relationship. Periodic industry surveys indicate that sites want to be appreciated and recognized for their hard work on increasingly complex protocols. They prefer to work with sponsors who set realistic patient enrollment goals, have an efficient contract and budget negotiation process, maintain a fair payment schedule, maintain good communications with the site, and have well-trained monitors.

  This is a tall order, but putting processes in place to achieve at least some or all of these goals is a commitment that more sponsors seem willing to make. "Sponsors are seeking a winning formula for interacting with sites. Generally speaking, the relationship is strained at best," comments Scott Ballenger, president of Trial Acceleration Institute (Spring House, PA), a consultancy dedicated to improving cycle times. 

Sanofi-Aventis is one sponsor that is launching a broad-based plan to enhance site relations as a key strategy for improving site performance. "We are on a mission to be the Sponsor of Choice to our sites," says Kim Oliver, regional operations zone lead and head of the company's site improvement project. Oliver explains that the company has always worked well with its sites but is seeking to optimize that relationship. 

To start the process, Sanofi-Aventis conducted a site satisfaction survey in late 2006 of the U.S. sites with whom it is currently working. Of the 5200 sites surveyed, 799 responded, yielding a 15.4% response rate. "This high response rate is an indication that our sites are interested in what we are asking and they want to help us get better," Oliver says. The survey had two components: a 39 question multiple-choice section with answers such as highly agree, moderately agree, slightly agree, etc., and another section with text fields, inviting respondents to share their thoughts and feelings. "They told us exactly what they felt, and they wrote volumes," notes Oliver. 

Results of the survey showed that sites pegged the following areas with room for improvement at Sanofi-Aventis:  

To address these issues and to make the kinds of real changes that sites would recognize and appreciate, the company launched Operation Cupid—Commitment by the U.S. CRU (clinical research unit) to Partner with our Investigators Daily—in second quarter 2007. As of this writing, Operation Cupid is an internal name, and the company may be considering other names for external branding. 

To begin Operation Cupid, the company assembled 12 to 15 small interfunctional teams to address the areas of greatest need. The teams are composed of in-house clinical research associates (CRAs), regional CRAs, project leaders, regional managers, and clinical project assistants. "We need all of their input because the relationship between the company and the site is about more than the CRA," commented Oliver, "it's about all the interfaces between us and the site." 

Through Operation Cupid, much effort is being directed at improving the top four areas of concern. Regarding communication, sites seem to want the simplest of things, such as more responsiveness, better phone manners, follow-up after a study concludes, and most importantly, knowing whom to call with specific questions during the course of a study. Regarding investigative payments, the survey revealed that sites do not necessarily want larger grant payments; rather, they want to understand the internal process and to be paid in a more timely fashion. To improve the study startup process, sites report that they want help submitting regulatory documents so they can begin work on the study as quickly as the company would like them to. For site and staff training, sites want the sponsor to invest time, resources, and support for protocol training, as well as continuous high-quality training throughout the course of a study. They also want the opportunity to retrain as needed through e-learning and remote training venues. 

Wyeth is also engaged in building better site relations through its Site Management Breakthrough Initiative. Launched in January 2007, the company started by conducting an internal as-is assessment. "We looked at how we felt we were operating and identified our issues in recruiting sites, managing sites, and working with investigators," explains Michael Smith, vice president. 

The assessment turned up two key findings: first, that the company inundates its sites with infrastructure. "There are too many levels of communication. The sites are frustrated because they don't know whom they should call or how to follow up," Smith says. Second, sites have lots of technology issues surrounding EDC, whereby they often have multiple systems working simultaneously to accommodate trials for various sponsors. In the short term, there is no easy solution to the dilemma of multiple EDC systems, as sites will continue to work for many sponsors, each with its own EDC system. 

Both parties benefit from intentional friendships, and nowadays CRAs are key to this cordial effort.

Applied Clinical Trials-01-01-2008

It's Official: CT Directive Poses Problems

Lights, Camera, Adaption

ACT Summit Highlights First-in-Man Trials

Changes and Challenges in the Year Ahead

eShowcase: ClinicalAnalytics Version 4.0 Enhanced

An Improved Trial Model

Tackling Racial Disparities in Research

Good Site and Sponsor Relationships Pay Off

DIA Brings Canada's Best Together

eShowcase: Oracle Initiatives Focus on Drug Safety

Two Decades of Change for PROs