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SITES : Reducing the Challenges of Study Coordination  Workload Measurement Instrument for Cancer Trials  RECRUITMENT : African Americans in Clinical Trials  Also in this issue : 2011, A Challenge for the Biomedical Research Community?, Joint Manifesto Tries to Address Vicious Cycle, Discontent with IRBs, R&D Success Rate Continues to Fall

Applied Clinical Trials Digital Edition - January 2011

With New Year's resolutions still fresh in the mind, many may have put "lose weight" at the top of their list. Along with gym enrollments, those who are very overweight may have hoped to add a prescription medication to their regimen. However, what started out in 2010 as potential new therapies for obesity has turned into a murky future for drug development in this area. Sponsors with potential therapies at the starting gate were derailed by safety issues and even an already approved and marketed drug—Meridia in the United States—has been pulled voluntarily by its manufacturer, or forced out by global regulatory authorities. 

In January 2010, the EMA suspended the marketing authorization for sibutramine, known as Reductil, Reduxade, and Zelium, across the EU. This was based on the results of a European postmarket request for a cardiovascular outcome study due to concerns raised in the clinical trial data. The FDA then evaluated and met on the SCOUT data in September, and asked Abbott Laboratories to voluntarily withdrawal Meridia from the market on October 8. In mid-November, India's regulatory authority, the Drugs Controller General of India, followed suit and suspended formulations related to sibutramine and r-sibutramine imports and manufacturing.  

Paul Aftring, VP and Global Head, Endocrine and Metabolic Disorders at i3, told 

that the current climate for obesity drugs is "difficult to say the least." The reasons why are directly related to these various cardiovascular safety issues. However, when it comes to recruitment, potential participants aren't turning away from clinical studies, even with the historical cardiovascular events related to these drugs. 

"The condition is extraordinarily prevalent," said Aftring. "Finding subjects to participate is easy." Where the trial becomes challenging is in subject retention and global trials issues. 

"Obesity specialists are well aware that this is a population that is hard to keep engaged," explained Aftring. Much like any other weight-loss approach, if there is limited or slow success, the person will lose interest. But in a clinical trial, participation to the end of the trial is required for the data and the control group. 

Aftring suggests using small rewards such as pedometers, which can monitor activities even after the trial is over, or cookbooks that can help with diet. "You have to make sure you aren't creating undue influence," said Aftring, "but these types of things can be used." But outside of useful tokens, what else can be done for the obese subject? 

Since not all investigators will be obesity specialists, there is a need to educate the site staff on engagement and retention. Engagement can come in the form of follow-up phone calls, compliance to the study, and encouragement on achievements, no matter how small they are. There will be weight loss achievements because all subjects in an obesity clinical trial will still be required to comply with the standard of care, which is diet and exercise. Specifically, these trials call for all subjects to limit their dietary fat to 30 percent. The difference, of course, is some will be on placebo and others on the experimental agent.  

In order for the data to be measurable across a global trial in obesity, however, is where conduct can become complex. How does a measurement becoming equalized when a subject is instructed to take the agent before a meal— members of one culture might eat a number of small meals during the day, and a large meal at night, while another culture might feature three large meals per day. "The challenge is how to get consistent results," said Aftring. "There are local nuances that need to be addressed." i3 wrote and posted an article to its website at 

www.i3global.com/spotlight/spotlight03232010

 that discusses these global issues in detail, from variability in diet and exercise to developing those educational materials involved across cultures.  

With the challenges of a negative risk-benefit ratio surrounding obesity drugs due to increased cardiovascular events, future development may lie in the comorbid conditions in cardiovascular disease and type II diabetes. Industry experts predict a dearth of drugs for obesity, a similar 10-year span that occurred with the fen-phen safety issues in the 1990s. Aftring notes there is much more activity on the diabetes side of the endocrine equation. In the end, it may be that sponsors will focus on testing diabetes drugs with better risk profiles, or working toward obesity drugs that have a novel mechanism. However, trial managers can take the aforementioned advice from Aftring for cultural nuances in a global trial. Applying local and cultural norms in any trial is necessary, as well as retention and engagement strategies. These will not be lost in current or future diabetes and related trials.  

Therapeutic Corner

Obesity Wins One, but Rest of Field Uncertain

Throughout the entire clinical development, who has the most interaction with prospective and active subjects? Who is primarily responsible for the quality of the source data that ultimately decides the approvability of all biopharmaceutical products?  

Principal investigators were asked who satisfaction surveys should focus on during a study. Site Coordinators were named more than half the time, ahead of PIs themselves. 

Yes, the answers are identical: the site coordinator, study coordinator, or clinical research coordinator, whatever title you choose. These individuals are the keystone, the glue that holds the study process together. Without them very few patients would be randomized, informed consent forms would not be completed, site contracts would not be negotiated, data would not be entered, queries would not get resolved, and database lock would be delayed.  

Delay is the key point. Site coordinators help a study stay on track. Without good ones, hitting milestones would be nearly impossible. 

ISR dedicated an entire study (The Voice of the Site Coordinator— 

) to understanding site coordinator's experiences and perspectives on improving the success of clinical trials.  

Throughout the entire clinical development, who has the most interaction with prospective and active subjects? Who is primarily responsible for the quality of the source data that ultimately decides the approvability of all biopharmaceutical products?

Site Coordinators: An Untapped Resource

GCP training will come under the spotlight at the start of February, when the European Forum for GCP's annual congress takes place in Budapest, Hungary. 

The two-day meeting will bring together experts from a range of clinical trial disciplines to discuss the needs of the key players. The organizers' prime aims are to exchange national and organizational experiences and to devise constructive proposals for meeting GCP training needs. 

The European Forum for GCP's annual congress will take place in Budapest, Hungary; Livio Sinibaldi/Getty Images			

"Although the European Commission has established a comprehensive regulatory package to ensure that GCP principles apply to the conduct of clinical trials within Europe, it is very apparent that the practical implementation of this regulatory package differs between member states," state the organizers. 

Training must be appropriate for each partner, whether it is an industry or academic sponsor, ethics committee, competent authority, or investigator. This training is often inadequate, inconsistent, and too theoretical. This has to be addressed, as does the need to ensure that patients and the public are more aware of the benefits and risks of taking part in studies involving the use of rigorous standards, according to officers from the EFGCP. 

Two important initiatives being considered by EFGCP are the creation of a common curriculum and provision of certification and accreditation. The keynote address from Jean-Pierre Tassignon, MD, PhD, President of Crossover CRI (Zug, Switzerland), will ask whether harmonized training standards are really necessary.  

The event, called "Certified GCP Training—Needs and Solutions," is being held February 1- 2, and is supported by the Hungarian Clinical Trial Management Society. Its seven workshops will address e-GCP training, how to teach clinical research to medical students, training of experienced investigators and responsibilities for training their teams, the suitability of SOPs as training tools, how to train risk-benefit assessment in rare diseases, the contribution of patients in ethics committees, and special training for research involving older people and geriatric patients. 

The conference will also include an update on the PatientPartner project to be given by Cor Oosterwijk, PhD, from The Netherlands. PatientPartner is a three-year European Union FP7 (Seventh Framework Program) project investigating, enforcing, and advising on the role of patient organizations in clinical trials (

). Its main goals are to make inventories of the needs of patient organizations; to identify and realize common points of action amongst all stakeholders by engaging in an active dialogue; to realize the European Network of Patients Partnering in Clinical Research (ENPCR); to create a European network for interaction with the other stakeholders in the clinical trial field; and to create European, patient-centred guiding tools and recommendations on how to create a successful partnership.  

PatientPartner organized a training workshop in Brussels on December 7-8, 2010, and in his Budapest presentation, Oosterwijk will present details about the results of the workshop. —

Global News

GCP training will be the main point of discussion at the EFGCP meeting in February.

EFGCP to Establish Changes in GCP Training

Recruitment of African Americans into clinical trials is going through another evolution. With global patient outreach far from peaking, the unchartered growth of outsourcing overseas for patient recruitment is beginning to raise genetic issues at home.

  As American pharmaceutical and biotech companies rapidly expand to other parts of the world, recession and acquisitions compromise efforts to recruit hard-to-reach American minority patients for clinical trials. 

African Americans make up the second largest minority group in the United States—increased by 13 percent between 2005 and 2006. More than 45 percent of America's population is non-white or classified non-Caucasian. In some states, African Americans can make up as much as 30 percent to 60 percent of the residents.

  Yet, too many clinical study results, related to diseases critical to African Americans, show as few as 2 percent recruitment of African Americans, or vaguely stated as 9 percent "other" or "non Caucasian."   

Illnesses such as asthma, diabetes, hypertension, HIV-AIDS, and certain kinds of cancer affect African Americans more than other people. Little is known about the ways African Americans respond to treatment for these and other conditions. Despite government regulations that require minorities to be included in federally funded research projects, African Americans remain underrepresented in these critical projects.

Most clinical research sponsors are aware of this shortfall, and admit there is a problem. Yet many don't specify or request even 10 percent to 15 percent of African Americans in studies unless there is a special protocol, or unless it relates to HIV-AIDS, sickle cell anemia, and certain cancers. Setting minimum requirements with your team is the first step in the complex chain to reach African American participants. 

With the 2010 US Census expected to assertively focus on hard-to-reach minorities and underserved populations,

  the results are predicted to reveal even higher numbers of minorities than in the past. If so, the omission of mandatory clinical recruitment policies regarding African Americans and minorities will be somewhat like playing Russian roulette with an entire population. Though efforts such as EDICT

  (Eliminating Disparities in Clinical Trials) has begun to recommend new policies, changing the present scenario requires due-diligence and creative partnerships, both within and outside of this clinical trial and cultural void. 

In a recent health disparities symposium on cancer, David Satcher, MD, PhD, Director of the Satcher Health Leadership Institute, Morehouse School of Medicine in Atlanta, GA, spoke on "A Right to Care." He outlined significant barriers to healthcare of African Americans in the United States that he calls the "UNs:" uninsured, underinsured, underserved, and underrepresented.

Satcher stated that 40 million Americans are uninsured; 25 million underinsured. "Doctors tend to clump together where it's comfortable and usually it's not near the underserved," he said.  

"Over the past 10 years, black doctors (and nurses) are underrepresented in our healthcare system, and we are not making significant progress in that area." When seeking healthcare or in clinical trials, it is important that a person see themselves represented in the healthcare system. 

Eliminating racial disparities in clinical trials begins and ends at the top, with education. Educating the doctors and medical providers is a start, but it's not enough. It is critical to begin the educational process with sponsors of clinical trials. They could set the bar higher by first requesting, and then requiring larger numbers of African Americans pre-screened for all trials for diseases critical to this population. 

The problem with recruiting and retaining African Americans in clinical trials should be viewed as the "problem with us"—those responsible for clinical recruitment, rather than the "problem with them." Finding solutions should be a multi-level, multi-tasking function of the sponsor; recruitment team; clinical research organization's or patient research organization's vendors; project managers; and local site investigators, all working in concert toward this goal.  

With new drug discoveries in the pipeline, many offering hope for African Americans,

  recruiting them requires new strategies that provide ground-zero opportunities across the board, and with the highest ROI—one that will bridge cultural gaps.  

The investment return for expanding minority outreach can dramatically increase if that expansion includes strategies for a closer, personal, and more trusted outreach to venues such as black churches and community health partnerships. This outreach could logically make the difference between 2 percent or 10 percent recruitment of minorities in that community.  

If sponsors of trials want to build and sustain trust for future trials, they should tap into community health networks that already provide local health education about diseases. Look into trial outreach through black professional newsletters, flyer distribution to partnered church health initiatives, and community organizations. Use site investigators as resources. This will make a trial more important to the community than other trials trying to recruit from a distance. 

Sometimes, for example, local site investigators are already involved with these organizations. A community-involved site investigator means there is already an important trust factor present. Something as simple as a brief site investigator survey could produce a treasure of resources. 

Where site investigators are involved in the community, there will be a greater access to African American patients. Likewise, patient recruitment of this population could increase dramatically in key states

  if project management is focused upon identifying, training, and funding African American physician investigators already involved in the community.  

A new ground-zero field research, called C.E.D.R.I.C.T., pronounced CED' rick, [Table 1] (Coalition to Eliminate Disparities and to Research Inclusion in Clinical Trials) has evolved to gather face-to-face data on African Americans nationally. The initial surveys observed three obstacles that must be tackled for better patient recruitment. It also has observed three keys to addressing these obstacles. The obstacles are trust, interest, and opt-in opportunities. The keys are disease, patient, and community education. 

Table 1. C.E.D.R.I.C.T. evolved to gather face-to-face data on African Americans nationally. 

Developing an outreach to recruit minorities for clinical trials, while at the same time creating trust often relies on media data that does not provide a true picture of potential African American clinical trials participants. So we take the standard shortcut when looking for minorities: Advertise in black media.  

Advertising is a proven outreach strategy and it works on many fronts. However, the obstacle of trust cannot be overcome solely by talking to African Americans about a clinical trial between R&B songs. Trust involves an "in-your-face" approach to such an intimate undertaking as participating in a clinical trial. And for many minorities this is not an option.

Elise D. Cook, MD, Chair, Minority and Medically Underserved Subcommittee, for SELECT trials

  was part of the team that developed focus groups to get input from men in target population(s). During the study, ways to enhance minority recruitment were explored and three one-day minority recruitment workshops were developed, along with community partnerships with NBLIC II and others [see sidebars]. They found that trust was built among participants where open and ongoing communications evolved, and continued with participants even after the trials ended. 

Developing ethnic-focused communication tools

Tools for developing ethnic-focused, community-based project management could be as simple as creating a selection of educational trials flyers, posters, brochures, or pamphlets for distribution by your "community-involved" site investigators in their communities.  

Familiar, face-to-face exchange and distribution of culturally-sensitive information, both in doctor's offices and the community, presents huge recruitment opportunities toward establishing trust among African Americans for multiple diseases.  

Support project management by providing what is known as an 800 ERN (Educational Referral Number) to buttress the unfamiliar pre-screening interview. The ERN allows participants to ask questions and allows for smoother transition into pre-screening. Utilizing an 800 ERN throughout the recruitment campaign could be a positive, escalating educational tool. 

Appropriate city and site selection is critical. Unfortunately, it's often easier and quicker to stick with the familiar sites. If you are looking to recruit African Americans, selecting a site in the suburbs, as opposed to one with a heavy concentration of African Americans, can present obstacles for participation. Finding sites that are within a comfortable distance from African American communities could be a matter of finding African American site doctors and then helping them to outreach for your trial. 

Sponsors could increase their chances for successful minority recruitment by making mandatory a percentage of investigators who are both African American doctors as well as non-minority physicians in areas with large African American patient bases. 

 Editor-in-Chief Lisa Henderson, aptly noted in May 2008 that "trial availability in that community; physician participation in the trial; and finally, being able to meet the criteria," were elements in successful recruitment of African Americans in an oncology trial.

Sparking interest is an elusive obstacle that is best facilitated through site community partnerships. The question arises, "If 30% to 70% of (minority subjects) say they'd be willing to be in a clinical trial...why do so few actually enroll?"

  Of the African Americans surveyed, over 40% stand firm on willingness to participate in clinical trials if someone asked them. However, 92% are firm about their willingness to participate if they had more information (education) 

 they are called to pre-screen. Clearly, this is an important key. 

Creating an interest in clinical trials participation among African Americans requires face-to-face exchange for maximum effectiveness. It then becomes the question of how to develop techniques that impact African Americans targeted for inclusion. The residual benefits of shifting a small percentage of the site project management resources to a community ethnic-focused campaign will translate to a greater ROI on current and future trials. As FDA guidelines become more inclusive, this shift will also avoid wasting time and money backtracking later in order to recoup minority participants for final drug approval.  

With the new Health Insurance Portability and Accountability Act (HIPPA) regulations, outreaching to gain minority interest in clinical trials without perks and incentives requires building strong community partnerships. Often this is done directly at the project management and site investigator levels.  

The third obstacle, creating opt-in opportunities, directly impacts patient recruitment vendors and site investigators. Influencing African Americans to opt-in to a database or referral list for trial participation can be site-based, event-based, web-based, or via sponsor's patient recruitment vendors.  

When trial sponsors outsource to clinical and patient recruitment organizations, they are hoping these vendors are able to pull their trials across the invisible line of "minimum requirements" for African Americans and minorities. For some trials (and a few diseases), this happens. Taking responsibility for minority patient recruitment at the beginning helps sponsors and project management teams take control. 

Clinical trial participant databases identified as exclusively African Americans are rare. However, one recent educational outreach that evolved from the 2009 C.E.D.R.I.C.T. field research is, "African American Health Matters." African American Health Matters is an opt-in mobile health text message program that sends health reminders and tips to over 25,000 subscribers about selected health matters. Fifty-eight percent of this audience is not on the Internet, but 84 percent have cell phones.  

Text messages also offer toll-free numbers and websites to find disease educational materials, clinical trials reminders, and positive reinforcement messages designed to help participants maintain a positive mental attitude, an important element of good health. 

Sponsors and recruitment organizations should adhere to quality checks of their minority patients and physician databases. Vendors should keep updated information about targeted African American participants and doctors for referral to trials. Look at track records. Whether performance-based plus community advocacy or advertisement-based recruitment, the yardstick for a vendor's ability to recruit for multiple racial populations is database development of specialized audiences. 

Sponsors should require "minimum goals" for recruiting African Americans in all US-based trials. The national average population of African Americans is around 12%, and over 100 cities have more than 30%. With these numbers, recruiters should consider requiring at least 10% participation for diseases with high mortality rates in this population. This requirement will present new recruitment opportunities  and offer increased education for critical diseases such as diabetes, hypertension, cholesterol, asthma, arthritis, obesity, and tobacco use.  

 In C.E.D.R.I.C.T.'s initial field surveys, other diseases were found to be of interest: orthopedic, cardiovascular, prostate related, breast, lung and colon cancers, gastric, menopausal, post menopausal, addiction, and depression trials. The point is to reach out initially with multiple diseases in multiple cities in order to identify your new patient populations. You'll then find the community hierarchy that offers access for future trials.  

Disease, patient, and community education

The obstacles are not insurmountable to recruiting African Americans into clinical trials. However, the obstacles must be overcome to avoid playing Russian roulette with this population. How? By initiating proven market strategies that work on many levels. When a company is willing to give minority recruitment more than a cursory glance, there are keys that will help them move forward: 

 Start with disease education related to the trial. African American churches with health ministries score big points for trust and openness. For a trial targeted to grass-roots participation, a study flyer with trial and disease facts, and ERN numbers for pre-screening consultation is extremely valuable information at African American churches or local health fairs. 

 Follow up with more patient education about the clinical trial being conducted. This can be done with various clinical trials recruitment outreach tools such as trial information on black websites and community media that cater to African American audiences, phone surveys, web, or e-mail announcements and mobile messaging. Paid advertisements can support this effort, but should never be used as the primary recruitment mechanism. Also, recognize the many community levels for event ads and outreach.  

Feature Article

Recession and acquisitions make recruiting America's second-largest minority even harder.

African Americans in Clinical Trials

As the glitz and warm goodwill of the festive season evaporate, drug firms and drug regulators are once again faced with the chilly reality of their differences of view, still largely unresolved as we move into the second decade of the 21st century. The clinical trial community is one of the principal victims of these differences, pincered between ever-increasing demands for demonstration of value and ever-tighter budgetary constraints from cash-strapped sponsors.  

The problem is depressingly familiar: growing healthcare demand, rising healthcare costs, tougher drug-launch criteria, squeezed company revenues, and pressure on R&D budgets—at the same time, drug development becomes harder and more expensive. What makes it all the harsher in this unhappy new year is that the economic downturn is biting severely into both public expenditure and private-enterprise profits. 

Two luminaries of the European pharmaceutical scene—one from each side of that traditional divide—made an attempt to forge a new approach as the old year came to an end. Andrew Witty, the CEO of GlaxoSmithKline and President of the European Federation of Pharmaceutical Industries and Associations, and one of Europe's top regulators, John Dalli, the European Union's Commissioner for Health, issued a sort of joint manifesto that tried to square the classic vicious circle.  

Their starting point was that policy-makers and the pharmaceutical industry across the European Union share the goal that all citizens and patients in Europe should enjoy equal access to the right medicines and vaccines. They offered a vision of the pharmaceutical industry, policy makers, health insurers, patients, and others, working together to achieve that objective. Success, they claimed, would result in healthier citizens, enhanced competitiveness, more balanced budgets, and fair reward for innovation. "Valuable innovation can transform lives," they agreed. 

A noble aspiration. At the broadest level, the need for greater equality is clear—as Dalli and Whitty remarked. They pointed to the beneficial impact of earlier diagnosis and new treatments on cancer, where incidence is increasing in the EU, but mortality is decreasing. "There is significant variability in patient access and in relative survival rates," they went on to note. "Similarly, we see wide variability between member states in the speed with which valuable innovative medicines become available to patients, and then further variability in uptake between member states and between disease areas." 

Aspiration is one thing. Delivery is another. As the two European pharma champions acknowledge, the task of delivering equality across Europe is not easy. "Health services everywhere face enormous challenges. Governments are understandably struggling to cope with rapid demographic change, the pace of technological change, and unbridled demand for healthcare. The current financial crisis exacerbates the difficulty of balancing desire for healthcare equality with the need for financial management."   

Against this background, they go on, "governments need to maximize public health outcome for a given budget, and to make choices." 

This is the difficult bit—for pharma companies struggling to get new products onto the market, and equally for health authorities harangued by their publics. 

European governments are focussing on value for money, and rely increasingly on processes like health technology assessment for decision-making. Dalli and Witty both say that this is appropriate, but there are reservations and hesitations. 

"HTA requirements in different member states vary considerably, which causes complexity for industry. The ongoing fragmentation of healthcare delivery in Europe introduces further challenges," they remark, in a bold display of diplomatic harmony. 

But as they advance in their argument, the underlying tensions inevitably emerge.  

"In this challenging climate, it is vital to achieve the best results for patients across the European Union, for public budgets and for industry," they say. They speak of "an equilibrium" between the needs of these different players—but in the same sentence they add: "with patients put first"—immediately suggesting some disequilibrium in the priority to be allocated to each player. Reading this, it is impossible to resist the thought that all players are equal, but some are more equal than others.  

From that point onwards, their joint manifesto starts to fray, with its separate threads stitched tenuously together only by the deployment of well-meaning generalizations that studiously avoid confrontation on the difficult details.  

"All stakeholders need to change the way they think and act, with 'health for all' achieved collaboratively at local, national, and European level," they chorus blithely—and innocuously, since the appeal is so vague as to be meaningless.  

"'All for health' should be the key enabler—the more institutions work in a trusting environment, the more likely the right approaches can be developed," they warble happily, allowing sound to triumph over sense. 

Where the manifesto addresses the distinct needs of each "stakeholder," it does so in the same well-meaning and inoffensive terms. "Industry must be a genuine partner to governments and their agencies," it trills. Who could take exception to its brotherly expressions of mutual understanding? Industry "must deliver new medicines and vaccines that address unmet patient need and have demonstrable value." Well yes, of course. And how? "This means getting R&D right—reversing the decline in productivity and delivering medicines that match the health needs of the population." Not wrong, of course, but not sufficiently right either to bring any illumination into the dark realities of this debate. Similarly, "industry must increase the transparency of what it does and be a source of ideas to governments, including on increasing funding and more efficient use of budgets." Insofar as this highly-nuanced and carefully selected language conveys anything at all, it seems to amount to little more than an offer to industry to connive with governments in engineering its own downfall.   

As a concession, as it were, to industry sensibilities, the passage concludes: "The pharmaceutical industry is hugely innovative. If governments work to support innovation, the industry will deliver the next era of revolutionary medicine." 

That blandly optimistic formulation is followed by another: "Governments have the key responsibility for delivering equitable healthcare. It is possible for them to encourage and reward therapeutic progress, while maintaining core characteristics like equity, public funding, and strict regulation." It may indeed be possible. What would be more interesting would be to know more about how it is to be done.  

The recipes proposed for success remain largely at the same level of pious exhortation and comfortable banality. "We must create in Europe the right policy and regulatory framework." OK, what's next? "This requires that effective prevention and wellness programs are in place." Safe, but vague. "We must shift focus from cost to value, and set a strategic agenda that addresses unmet needs." Difficult to fault, but difficult to decipher, too.  

There is some attempt to grapple with the difficulties in establishing a sense of value—but again, without much real commitment to a discernible course of action. There is talk of "allowing industry to understand the type of added value that matters to patients and will be funded by payers," and of "a shared understanding of value" through "high quality dialogue between industry and authorities." Dalli and Witty (a coupling of names that faintly suggests a comic duo from the age of music hall, even if their routine often seems short of a punch line) see an important role for health technology assessment in ensuring that "the government does not pay for medicines that do not work but that equally, patients get access to medicines that may help them." But how it should play this role is less clear. "Closer cooperation" is one recommendation, immediately countered by the remark that "a single approach in the EU is undesirable, since member states will want to make decisions according to their own priorities." 

At the same time, "the current diversity and overlap leads to unequal access for patients, complexity for industry, duplication of work, and unnecessary red tape." This tangled series of observations is hardly clarified by the conclusion that "While the final decision has to remain national, in particular on price and reimbursement, we should explore a common methodology on the clinical aspects of health technologies in Europe which might then be used for assessments of relative efficacy and effectiveness at European level." 

So if clinical trial and pharmaceutical professionals were hoping that this unusual outburst of ecumenism in Brussels was going to make things easier—or even just clearer—in the new year, well, I'm very sorry. But happy new year anyway.  

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

View from Brussels

An alliance between two European leaders gives hope for unison but falls short on solutions.

The New Year Brings Same Old Battles

It is increasingly evident to all parties involved in the sponsorship and management of clinical trials that a better understanding of the time, staff, and financial resources required to conduct clinical trials is necessary. The increasing use and complexity of multi-modality treatment regimes, the rising costs of clinical trials, the emphasis on the efficient use of available resources and adherence to Good Clinical Practice (GCP), and increasing regulatory requirements and demands for quality assurance/control, have resulted in an increased focus on workload issues. Failure to address these issues has resulted in research staff using unproven methods or a simple estimation for determining workload, leading, in some cases, to unrealistic expectations, excessive workload, or inefficient use of resources.  

The EORTC Clinical Research Coordinators Group recognized the importance of addressing this problem based on understanding the tasks involved, the time requirements, and the resources necessary to effectively and efficiently conduct clinical research. The development of a workload measurement instrument (WMI) was seen as a means of providing a tool by which individuals could estimate more accurately the time and resources required to participate in clinical trials. The initial project was supported by the EORTC and funded by a grant from Fonds Cancer (FOCA). 

The WMI was developed in seven stages and the first stages: development, validation and revision of a draft checklist of trial related activities, drafting of the WMI, a feasibility pilot study, and analysis and revision of the trial related tasks incorporated into the four modules previously outlined in an 

 article that appeared in June 2008, titled "

  Coincidental to the development of the WMI, Jacqueline Briggs had developed a complexity tool for assessing the complexity of a study prospectively.

  It was agreed that, in the longer term, a joint workload and complexity project would aim to independently validate and link together the WMI and the complexity tools.  

This article describes the seventh stage of development of the WMI; a prospective study using the WMI to collect data for the purpose of validating the four WMI modules.  

The preparatory phase identified the specific actions necessary and the financial and staff resources required to complete the prospective study. The Steering Committee members presented the prospective study outline to a meeting of National Cancer Research Network Managers and identified the networks that would be willing to collaborate. Expression of interest questionnaires were sent out to all UK network managers and to research staff in several European centers to identify research staff and potential trials for inclusion in the prospective study. Fifteen UK networks and a center in Ireland initially agreed to participate in the study and, of these, 12 networks returned completed modules as part of the prospective study.  

The prospective study focused only on research related activity and not on what would be considered routine care. Workload was only recorded for research staff working on the trials and excluded investigators, pharmacists, day care staff, etc. These staff members were excluded as it was felt that it would be difficult to collect accurate workload data from such a wide range of staff and this was accepted as a limitation for the purposes of this study.  

As the joint project had been extended to include complexity the four WMI modules (Module 1: planning stage; Module 2: implementation stage; Module 3: trial data management stage; Module 4: closure/final stage) were reviewed. In order to facilitate the validation of the complexity tool and create the necessary links between the two tools, it was agreed to divide Module 2 into two modules: 2a recruitment and treatment and 2b treatment and follow-up.  

A data collection period of six months was agreed and the time frame for completion of data collection was October 2005 to May 2006. Prior to the commencement of the data collection period, three training days were held in Newcastle, London, Nottingham, and Wales to roll out the study to the interested participants. Forty-three research staff attended these training days. Information was provided individually for staff unable to attend the training days.  

From the training days and returned questionnaires, a number of trials were selected on which the prospective study would focus. For modules 1 and 4 it was agreed that any trial in set up or at the closure stage could be included due to the small number of trials likely to be at these phases during the six month time frame. For modules 2 and 3, trials covering as many tumor types, treatment modalities, and study types were selected to ensure as inclusive a range of activities as possible. A total of 36 studies were identified and included in the prospective study. 

Guidelines for the completion of each module were developed and circulated, together with the four modules and the list of identified trials, to 70 collaborators, covering 15 networks that had agreed to participate. Collaborators were asked to record the time taken, in minutes, for each individual task or subtask undertaken as identified within the modules. A subsection—other—was included for recording any additional activities not identified within the modules. A separate section recorded the hospital name, trial name and number, the date for data collection commencement and completion, the reason why data collection was ended, and whether more than one form had been completed. This allowed us to identify the total period of data collection and subsequent analysis of workload for a single trial visit or over the course of a trial period.  

 Data was entered into a database developed in conjunction with the NCRN IT department based on all the identified tasks and subtasks of the WMI modules. The NCRN agreed to provide staff in order to complete the data input and carry out some preliminary data analysis and a system for quality assurance of the data was agreed upon.  

The Steering Group met regularly to review the progress of the prospective study, and as returned modules were received, to carry out the initial quality assurance procedures. All returned modules were double-checked to ensure accuracy, and when tasks or subtasks were entered in an incorrect section these were noted and revised prior to entry onto the database. Incorrect or unclear entries were deleted. Regular contact and feedback was maintained with the collaborators throughout the study by e-mail, newsletters including answers to frequently asked questions, and presentations at Cancer Research Network Managers' meetings.  

A total of 414 completed modules were returned from collaborators from 27 hospitals covering 12 UK Cancer Research Networks. Three networks or centers did not return completed modules due to merger of networks, shortage of staff, or excessive workload issues. Data was returned on 35 of the 36 studies identified for inclusion in the prospective study. Table 1 shows the modules returned. 

Table 1. A total of 414 completed modules were returned from collaborators from 27 hospitals covering 12 UK Cancer Research Networks. 

As part of the analysis process a series of assumptions were made. These included: research staff were experienced and trained and not involved in the actual delivery of treatment, research activity was additional to standard treatment, and hospital support services and standard equipment were available and accessible to research staff. 

Cumulatively, 130 changes were made in the 74 subtasks (Table 2). These changes included transfer from one subtask to another where an entry was incorrect, deleting investigators, and separating out multiple patient visits into individual visits. The highest numbers of recording errors (9, 15, and 16) necessitating transfer related to the recording of administration activities in other subtasks rather than administration activities. 

Table 2. Cumulatively, 130 changes were made. 

Following extensive quality assurance procedures all tasks and subtasks within Modules 1, 2, and 3 were validated as relevant and appropriate with no tasks or subtasks removed. All subtasks were recorded at least once with a very wide range within each module. For Module 1, the most frequently completed subtasks were those relating to the preparation and submission of documentation to Ethics and Research and Development departments. Conversely the lowest recorded tasks related to organizing and attending meetings other than in-house meetings for information, training, and trial activation.  

For Module 2a, the most frequently completed subtasks related to screening for eligibility, informed consent, and sample preparation. This was consistent with the expectations and personal experience of the project group. The least completed subtasks in Module 2a related to liaising and verifying radiotherapy dose reductions and missed treatment which was anticipated given the very low numbers of radiotherapy related trials included in the study.  

For Module 2b and 3, the most frequently completed subtasks related to case report form completion, photocopying and sending trial documents, the preparation and submission of trial amendments, and updating study documents following amendments (Table 3). 

Table 3. For Module 2b and 3, the most frequently completed subtasks related to case report form completion, photocopying and sending trial documents, and the preparation and submission of trial amendments. 

Two major revisions were identified as necessary. The first change related to the recognition of the importance given to administration and communication by the collaborators. The section "other" consistently included additional administration and communication and it was agreed that these two activities should be included as subtasks for all main tasks in the final modules. In total, 110 transfers were made to administration main tasks and 230 to administration subtask activities; 38 to communications main task, with 100 to communication subtask activities. The second change was the recombination of Module 2a and 2b with specific sections relating to consent, treatment, and follow-up incorporated—confusion had arisen in completion of these as two separate modules.  

Modules 1, 2, and 3 of the workload measurement instrument have been validated and are now complete. These modules are available in their entirety online in PDF format at 

 as part of the online version of this article. Module 4 has been revised in accordance but would benefit from validation as part of a specific prospective study as trials reach closure stage.  

It is acknowledged that there were limitations to the prospective study that included the short data collection window of six months, the exclusion of principal investigators and other associated staff from the data collection exercise, compounded by the difficulty associated with specific local hospital issues all had potential to confound the data collected. It was accepted that these factors would contribute to workload but would not necessarily alter the tasks and subtasks identified for inclusion in the modules and, therefore, such confounders were not considered significant for the purpose of the WMI validation. For hospitals or departments undertaking a workload analysis in the future it would be appropriate to take these confounders into account. 

This WMI was developed to be a generic tool and can be used locally, nationally, or internationally to review the trial workload of an individual researcher, team, hospital, or network of centers. It should inform discussions at all levels and allow centers considering implementing new or additional clinical trials to accurately evaluate the associated workload and to allocate staff and resources accordingly.  

 is Head of Discipline at Division of Radiation Therapy, School of Medicine, Trinity Centre for Health Science, St. James' Hospital, Dublin 8, Ireland, e-mail: 

 is Clinical Trials Team Manager at Mid Trent Cancer Research Network, Nottingham City Hospital, United Kingdom. 

 is Head of Cancer Trials at University College London Hospitals, NHS Foundation Trust. 

 is Stroke Research Network Manager at Peninsula Stroke Research Network, Royal Devon and Exeter Foundation NHS Trust, Exeter, United Kingdom.

1. Julie Berridge and Mary Coffey, "Workload Measurement," 

2. Jacqueline Briggs, "Real World Workload Needs: Developing a process and management tool for scoring complexity in cancer clinical trials," 

Applied Clinical Trials: Oncology & Clinical Trials in the 21st Century, 

It is necessary to understand the time, staff, and financial resources required to conduct clinical trials.

Workload Measurement Instrument

My personal frustration with institutional review boards reached a boiling point several months ago. A dozen IRBs had each reviewed a general educational brochure prepared by the Center for Information and Study on Clinical Research Participation (CISCRP). The brochure was not specific to any clinical studies and its focus was on explaining the risks and benefits of clinical trial participation. All IRBs had suggested revisions to the educational language. But only one of the 12 IRBs rejected it. The reason for rejecting the brochure: Educational material "...should not include the word 

My deep frustration was felt on many levels. The concept of "hope" is central to patients and their families wanting to consider and evaluate clinical trials among their options. Just as risks can be discussed openly and in a language that the lay public understands, general educational information must also openly and honestly acknowledge the potential benefits of participation. Why, you might ask, were IRBs even reviewing a general educational brochure when it falls outside their jurisdiction?

  As  an independent non-profit, CISCRP's mission is to provide public education to promote greater, more balanced and informed understanding and awareness of the clinical research process. This is also part of the overall mission of all human subject protection programs. By rejecting CISCRP's educational materials, was this IRB doing a disservice to the very population that it strives to protect? 

I'm clearly not alone in my frustration. A large and growing number of government and private-sector clinical research professionals are voicing their concerns and suggesting that our current human subject protection system is ripe for radical reform to change its antiquated, fragmented, bureaucratic, and over-reaching ways. A number of peer-reviewed articles have sounded the alarm including: Salim Yusuf's "Randomized Clinical trials: Slow Death by a Thousand Unnecessary Policies?"

  and Christine Grady's "Do IRBs Protect Human Research Participants?"

  This past year the Institute of Medicine has singled out IRBs as one of the top barriers to achieving efficiencies in clinical research. At a meeting that I attended in October, serious concerns were raised by academic and government leaders that failures of the IRB system are actually hindering the ethical protection of study volunteers. 

What's wrong with the system? Or, as some have rephrased the question, what's not wrong with it? Our nation's system of human subject protection programs has evolved into a complex regulatory and legal environment with 19 agencies in addition to the Food and Drug Administration (FDA) sharing oversight for protection of study participants. These agencies include the Social Security Administration and the Department of Homeland Security. After protracted debate, various agencies adopted the Common Rule in 1991 to harmonize human subject protection policies. Many agencies subsequently have added regulations while others have adopted inconsistent guidance on how to interpret the rule. The FDA chose not to even adopt the Common Rule, but did change its IRB and informed consent regulations to more closely correspond to federal policy. Adding to the confusion is the fact that IRBs must follow federal privacy requirements and state laws. Some IRBs must also balance compliance with International Conference on Harmonization (ICH) guidelines for studies outside the United States. This complex and crowded array of organizations have burdened IRBs with substantial inconsistencies in ethics regulations and the challenge of complying with many different and potentially conflicting requirements.  

Managing that burden would be enough. But there is the added weight on research sponsors to reconcile and coordinate wide and inconsistent variation in ethical review decisions across multiple IRBs. Current regulations require that each institution and investigative site involved in clinical research receive IRB approval. An ethical review of a single protocol for a multicenter trial requires that many IRBs conduct their own independent reviews. Reviews of the same protocol are not coordinated, they result in contradictory recommendations and outcomes, and they cost the research sponsor and study staff substantial time and resources. 

Clinical research professionals in both the public and private sectors widely agree that our current multiple IRB system is wasteful and causes unnecessary delays. In a recent 

 editorial, OHRP Director Jerry Menikoff, said that duplicative reviews not only provide "relatively few benefits," but the current structure actually might lead to "less-than-optimal protection" of those who volunteer to participate in research.  

Menikoff points out that the system results in individual IRBs feeling powerless to change the protocol when risks are identified. If one IRB has serious concerns about the study design, it usually results in that IRB leaving the study—either of its own accord or after being dropped by the sponsor—rather than resulting in a change to the protocol.  

A growing number of research sponsors and investigative site staff have expressed frustration and concern about IRBs overseeing more than their jurisdiction dictates. During the past two decades, IRBs have asserted themselves as gatekeepers of all interactions with patients and the public and the protectors of every possible potential or imagined harm that might occur during research. As such, IRBs often impose burdensome, impractical, unnecessary requirements in order to err on the side of extreme caution.  

Researchers and institutions complain that IRBs are overly expansive in interpreting regulatory requirements and that they focus on inconsequential details during reviews. Others complain that IRBs have been overwhelmed with obligations that have little to do with protection of research participants, and IRB members tend to focus more on procedures and documentation than on difficult ethical questions and serving patients' and the public's best interests.  

As clinical research has become more complex and demanding, the scope of IRB responsibilities has expanded to include compliance with privacy regulations, checking for potential financial conflicts of interest, and reviewing the methodological soundness and scientific merit of a study. Yet as IRBs are asked to take on more responsibilities, they have been criticized for becoming less effective and more susceptible to questionable practices. The now famous sting operation carried out by the General Accounting Office (GAO) in 2008 exposed a national human subject protection system vulnerable to unethical manipulation.  

IRB jurisdiction and authority is also virtually never challenged or evaluated. Few sponsors and investigative sites are willing to question an IRB's decisions out of fear that the IRB might scrutinize their proposal more closely or won't approve their research. The IRB's decision is the gospel—taken without question—despite the fact that nowhere in the regulations is an appeal prohibited. There is no data measuring whether IRBs are doing their job in protecting study volunteers from unnecessary risk of harm. The IRB system, which evolved from an institution-based structure with little accountability or data collection, lacks even rudimentary metrics for measuring its own success.  

There's no question that frustration among all stakeholders is intensifying and will eventually drive reform. But structural and procedural reforms are likely a long way off given such a complex, crowded, and heavily regulated system.  

Many ideas for IRB reform center around streamlining and creating a better, harmonized review process. One approach would be for sponsors to require the use of a central IRB as a condition for sites to participate in a study. Another proposal would change the system to impose more demands on early trials with new interventions while simplifying the oversight of commonly used interventions. Academic and government leaders have recommended collecting more data in order to measure IRB performance. 

The FDA and OHRP both support the use of a single, central IRB for multicenter research. Drug sponsors have increasingly contracted with central IRBs to review studies conducted by community-based investigative sites. Most universities and hospitals still opt to use their own internal IRBs when conducting both privately and federally funded research. OHRP is leading an effort to coordinate guidelines across various agencies, and plans to propose the creation of a single new agency to oversee all human subject research in the United States.  

As criticism and dissatisfaction grows, our national IRB system has been losing credibility and respect among regulatory agencies, clinical research professionals, patients, and the public. Extreme frustration may drive reform even sooner. After all, we owe it to patients and the public to get this IRB system, or a new one, working right. 

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

Title 21, Part 56, Section 102, 109  (US Government Printing Office, Washington, DC).  

2. S. Yusuf, "Randomized Clinical Trials: Slow Death by a Thousand Unnecessary Policies?" 

3. C. Grady, "Do IRBs Protect Human Research Participants?" 

Journal of the American Medicial Association

Clinical Trial Insights

Doing more harm than good will ultimately force human subject protection system reform.

Frustration with IRB Bureaucracy & Despotism

The implementation of complex, multi-site clinical trials presents challenges that make recruitment efforts, participant follow-up, and organization of staff critical to the success of the overall outcome. This article describes a unique staffing model utilized by the TODAY (Treatment Options for type 2 Diabetes in Adolescents and Youth) study, an NIH (National Institutes of Health) sponsored trial designed to explore treatment options for type 2 diabetes in youth. At each study center, the program coordinator (PC) and diabetes educator (DE) work together to implement the study protocol. A staffing model that provides this type of mutual support for two key members of the study team may decrease the burden customarily encountered solely by the PC in complex trials, and furthermore allows for cross-coverage and flexibility. To determine the degree of overlap and task sharing between the PC and DE across study sites, a self-administered survey was distributed to all PCs and DEs. Survey results as well as specific examples demonstrating an effective collaborative approach by front-line study personnel in managing various challenges encountered in study implementation are included.  

The TODAY study, which randomized its first participant in 2004, aims to identify optimal treatment regimens for type 2 diabetes specifically for adolescents and youth, as incidence has dramatically increased.

  The study follows an ethnically diverse group of 704 overweight youth (aged 10-17 at enrollment) with new onset type 2 diabetes (less than two years duration) for a minimum of two to six years at 15 clinical centers across the United States. The goal is to compare the efficacy of three treatment arms (two medication-only arms and one intensive lifestyle intervention combined with medication arm) on glycemic control.

  Study participants have routine medical visits every two months for the first year and quarterly thereafter. Interim medical visits are scheduled as needed for management of comorbidities or reinvigoration of diabetes management. 

The study participants are adolescents and their families who are coping with a new diagnosis of type 2 diabetes, and are also typically dealing with extreme socioeconomic challenges, psychiatric problems, and/or other chronic health concerns. Many of them have life circumstances that are inherently unstable; the recent diagnosis of a chronic illness creates additional disruptions in their lifestyles. It is not unusual for them to present a number of pressing issues at each study visit requiring extensive interaction with personnel with two distinct protocol-driven roles: PCs and DEs.  

Unlike the typical staffing model in large clinical trials where the designated PC assumes most of the responsibility for the daily work of implementing the protocol,

  in the TODAY study, the PC and DE at each study center work together to schedule and conduct visits, as well as collect outcome data. Although the study design and roles are protocol-driven, placing specific expectations on the PC and DE, the reality of carrying out each visit requires flexibility and task-sharing; the demands often lead to overlap in these roles at each study site.  

In order for this type of staffing model to be effectively implemented, teamwork and cross-training are essential and are supported by weekly conference calls and periodic study group meetings among all PCs, DEs, and staff of the Data Coordinating Center (DCC). The calls allow the opportunity to offer thoughts and perspectives on current study issues, as well as the opportunity to explore specific questions or challenges of protocol implementation. Both PCs and DEs attend study trainings that emphasize implementation of the trial and care of the enrolled population. This cross-training assures that the DE or PC can each help with the other's tasks where necessary, in order to facilitate timely completion of the study visits. 

There are limited published reports regarding effective staffing models of large clinical trials, and although the typical tasks performed by a research nurse

  have been described, the roles remain poorly defined. Little is known about workload distribution and job satisfaction, and many of the reports are anecdotal in nature.  

In the Diabetes Control and Complication Trial (DCCT), the PC role was filled almost exclusively by nurses. During the planning phase of the DCCT, the anticipated scope of duties of the research trial coordinator was unclear. In 1984, the second year of the trial, 21 trial coordinators (19 nurses, one physician's assistant, one dietician) were surveyed about their job activities, and subsequently reported diverse duties, including spending almost 50 percent of their time in medical management and 30 percent in administrative activities.

In the 1990s, there were few resources available for inexperienced PCs and the expectations of the role remained vague. It was not uncommon for studies to employ a model of hiring a PC with no clinical background, but who excelled in other skills such as problem solving, communication, and organization.

  In some studies, dieticians were selected for the PC role due to the necessity of delivering nutrition education as part of the study protocol.

In 2004, a survey of the standard tasks performed by 41 oncology clinical trial research coordinators showed that they all participated in activities such as recruitment, data collection, adverse event reporting, and audit preparation.

				  Those with a nursing background had significantly greater involvement than non-nurse coordinators in clinical care, such as assessment of response to therapy, adverse effects, and query resolution. In 2007, a report of survey results from 205 PCs (50 percent registered nurses) examined factors related to PC turnover. The findings revealed three major themes: the need for formal training, lack of promotion opportunities, and poor allocation of workload.

In the TODAY study, a combination of clinical management and administrative tasks are required at each study visit. In general, the PC is primarily responsible for administrative aspects of study implementation, such as IRB correspondence, budget preparation, supply ordering, equipment maintenance, data entry, and shipping of lab specimens. The DE's central responsibilities focus on medication adherence and adjustment, patient and family education, and clinical management of diabetes and its comorbidities. However, scheduled participant visits do not necessarily fall into discrete components solely requiring the skills of one type of staff member (clinical) or another (administrative). In addition, many study visit appointments occur during non-routine work hours in order to accommodate the participants' work and school schedules. It is neither practical nor feasible, within the constraints of staffing limitations, to always have both staff members available for each visit, especially when visits occur after hours and on weekends.  

To determine if the degree of overlap between the roles of the PCs and DEs across all sites was consistent with our expectations, given the complexity of the study visits, a questionnaire was developed and administered to all eligible PCs and DEs.  

 The sample consisted of 31 TODAY staff members (n=15 PCs; n=16 DEs). The authors, who represent DEs and PCs, were not included in the sample to avoid bias of the results.  

Reducing the challenges of study coordination in multi-site clinical trials.

Applied Clinical Trials-01-01-2011

Applied Clinical Trials Digital Edition - January 2011

Obesity Wins One, but Rest of Field Uncertain

Site Coordinators: An Untapped Resource

EFGCP to Establish Changes in GCP Training

African Americans in Clinical Trials

The New Year Brings Same Old Battles

Workload Measurement Instrument

Frustration with IRB Bureaucracy & Despotism

Collaborative Staffing Model

Business and News Update January 2011

Deteriorating Quality in Global Trials

Research Community Faces New Challenges

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