Not for the first time, the European Forum for Good Clinical Practice (EFGCP) has demonstrated its ability to keep its finger accurately on the pulse of what really matters in European discussions on clinical trials. That sensitivity for the hotspots was doubtless behind its decision to hold a workshop in Brussels in November on "options and challenges for ethical assessment in the clinical trial regulation proposal." Now that wise heads around Europe have had time to reflect on the European Commission's July proposal for new rules, one of the principal areas of potential difficulty that has been identified is whether ethics committees will buy into the radical approach of the draft regulation. 

Few readers of this publication will need reminding that among the changes proposed, all the existing EU requirements on ethics committee involvement in assessing applications for clinical trials authorization would be scrapped. This doesn't mean that ethics has gone out of the window. But it does mean that the European Union is planning to leave ethics considerations to national authorities—where, in strictly legal terms, they necessarily belong anyway, since the European Union has no writ on questions of ethics. Like taxation or social security, or indeed like most health matters, including drug pricing and reimbursement, ethics is one of those areas that has never been a subject on which the European Union has any authority.  

Accordingly, the proposed new clinical trials rules aim to achieve their intended streamlining by splitting the procedures into European and national component parts. The European level would consist of a harmonized list of documents to be submitted, an electronic portal for a single submission of an application (irrespective of the number of member states concerned), a coordinated scientific-technical assessment procedure, and tight timelines for member states to decide on applications. At national level, each member state will have to organize itself as it sees fit to integrate an ethics committee review within the timelines. 			

The commission remarked in its proposal that "a crucial element of the rules for authorization of a clinical trial is the clear distinction between aspects where member states shall cooperate in the assessment of the application for authorization of a clinical trial and those aspects where member states conduct their assessment individually, [which] includes aspects which are of an intrinsically national (for example, liability), ethical (for example, informed consent), or local (for example, suitability of the clinical trial site) nature."

If this description leaves open a lot of questions, that is because the planned procedure itself leaves open a lot of questions. The EFGCP workshop aims to start a dialogue that could help to answer some of them. The mechanism of this integration may require different solutions from one country to another. The workshop is looking at the practical implications of the proposal for ethics committees, and particularly at how to integrate all the aspects of the assessment into one decision per member state within the proposed timelines, without compromising scientific or ethical review standards, or levels of patient protection. 

Just how acute the challenge may prove to be is demonstrated by hostile reactions from ethics committees. One aspect of the difficulties was spelled out eloquently in a recent letter to the European Commission from the Chairman of the Ethics Committee of the Medical University of Vienna, Ernst Singer. Singer wrote to Stefano Soro, the Head of the Medicinal Products Unit in the European Commission, pointing out that merely in terms of the envisaged timelines, the commission's proposal was unworkable. "In its present form the regulation is not compatible with the current mode of operation of ethics committees, in particular in terms of scheduling," he stated.  

The scheduling envisaged by the commission is indeed tight. An application might lead to effective authorization in all member states concerned in as little as 20 days. "In order to meet the deadlines proposed in the new regulation the ethics committees meetings would have to be replaced, or supplemented by an ethics committees making decisions on a day-to-day basis," according to Singer. He pointed out that under their current schedule, committees such as his operate through regular monthly meetings of experts from a range of medical specialties, along with lawyers, patient representatives, and statisticians. "These meetings also provide the opportunity to discuss open points in the protocol with the principal investigator and the sponsor," he wrote—adding that in Austria "this is currently done within 35 days (including obtaining an external review)." He added that the meetings are not held on a monthly basis because the ethics committees do not want to meet more often, "but purely for inherent practical constraints: it is just not possible to have all the necessary highly specialized people available at all times." 

To meet the deadlines in the proposed new rules, "all involved experts would have to be constantly available"—which Singer points out is "highly unrealistic"—and it would become impossible to invite the principal investigator or a representative of the sponsor for discussion, or at any rate not in the presence of everyone concerned. "All this would unquestionably lead to a decline in the quality of the decisions made by the ethics committee, which cannot be in the interests of anyone." 

Singer provides some revealing statistics to support his arguments, highlighting the fact that clinical trials of medicines form only a part of the studies an ethics committee typically has to deal with. In 2011, he says, his ethics committee dealt with 233 clinical trials of medicines—comprising 19% of studies assessed. In addition, his committee dealt with 93 clinical trials of medical devices, and 901 other studies. "It would be wrong to assume that these 'other studies' are generally less challenging scientifically or pose a lesser risk to participants than medicinal product studies," he underlines. 

The consequences, Singer calculates, are that the proposed regulation would lead to the introduction of a dual standard: the majority of studies (in his committee's case about 75%) would be treated in the established way through monthly meetings, while for medicines, decision-making would have to occur on a day-to-day basis. "For the ethics committee (and the member state) this will definitely not facilitate procedures but introduce additional workload and two standards of review," he concludes. High-quality reviews would continue for everything but for medicines, which would suffer from a lower-quality review. 

The potential problems extend wider than just the timing of ethics committee review. Even those with long experience of clinical trials in Europe admit to finding it difficult to grasp exactly how the national approval process will function.  

"The proposal does not interfere with the member state's internal organization of the bodies involved in authorizing (or not) a clinical trial," the commission said in its proposal. "It is left to member states to define the organizational set-up to comply with the authorization procedure." Explicitly, the commission does not attempt to establish which national body or bodies approves (or not) a clinical trial, nor does it "regulate or harmonize the precise functioning of ethics committees, impose a systematic cooperation at an operational level between ethics committees in the EU, or limit the ethics committee's scope of the assessment to genuinely-ethical issue (science and ethics cannot be separated)." Instead, the proposal "leaves it up to member states to organize, internally, the attribution of tasks to different bodies." 

It is almost with a dismissive wave of the hand that the commission says "what matters is that member states ensure an independent, high-quality assessment within the timelines as set out in the legislation." In effect, the commission is saying that the European Union is prepared to do only so much to speed clinical trial authorizations: a single portal, and a single assessment procedure led by one member state, leading to a single decision, on which other member states are supposed to sign off within a few days.  

This is, as senior figures in the European clinical trials community have pointed out, a high-risk scenario. By leaving everything up to each member state to sort out its own approach to reaching a decision, the commission is exposing itself—and, more to the point, clinical trial sponsors—to the risk that not every member state will feel it is in a position to sign off. Constrained by time, and obliged to create new national systems for integrating all aspects of the assessment into one opinion, some members states may feel unable—or unwilling—to participate. If the streamlined system works, it could work well. But if member states are not prepared to play ball, it could prove disastrous. The subject merits plenty of exploration over the coming weeks and months.

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

Articles

View from Brussels

Will ethics committees buy into the radical new approach of latest draft regulation?

Taking the Pulse of Ethics Committee Views

Act Cover

A 2012 study conducted by the Tufts Center for the Study of Drug Development shows that academic centers and hospitals take significantly longer to initiate industry-funded clinical trials. Overall, it takes an AMC or hospital more than one year (12.9 months) on average from the pre-study visit to first patient in (FPI) the clinical trial. This compares with 7.9 months for community-based physician practices to complete the same cycle—nearly a 40% time reduction. The Tufts CSDD study evaluated start-up cycle times for 5,296 investigative sites participating in 105 Phase II and III clinical trials. The largest bottleneck is the time from when the contract is received by the center to the time that the contract is executed. AMCs and hospitals take nearly 73% longer than their for-profit counterparts—4.1 months on average versus 1.1 months. Cycle times from contract execution to site initiation, and from site initiation to FPI for non- and for-profit investigative sites are much closer, suggesting that AMCs and hospitals perform more competitively once they get through their less efficient administrative tasks. 

—Tufts Center for the Study of Drug Development, 

Survey Results of Start-Up Cycle Times

, (London, UK and Cambridge, MA) a global data-focused clinical research organization, announced the addition of 

 as Vice President of Pharmacovigilance and 

 as Vice President of Clinical Data Management to their management team. 

, PhD, Chief Operating Officer of SAFE-BioPharma Association, the strategic, non-profit collaboration responsible for the global digital identity and digital signature standard used in the life science and healthcare sectors. 

(Cleveland, OH) a clinical monitoring firm, announced the addition of seven new clinical research associates and one member of its business staff. The seven new CRAs are:

, MA. IMARC also announced the appointment of 

has been appointed Chief Financial Officer. Vickers was Vice President of Finance for the company and joined OmniComm in October 2011. 

, (Paris, France and Cambridge, MA) a provider of non-statistical clinical data analysis technology across life science industries including FDA, announced that it has appointed 

 (Tempe, AZ) an integrated site network in the clinical trials industry, announced the addition of 

 as Vice President of Quality Assurance. Mashburn will be responsible for the overall planning and implementation of quality assurance initiatives within CRA's 34 clinical research sites in Arizona, California, Colorado, Indiana, Iowa, Nebraska, and Nevada. 

(Malvern, PA) an eClinical products and life sciences consulting services company, has expanded its international operations in Europe and has named

as Senior Business Analyst in the UK office. 

as Executive Vice President, Business Development. He has global responsibility for the company's business development, marketing, proposals, and strategic alliance development, providing strategic leadership to drive the company's growth plans. 

• Clinical Trial and Consulting Services 

(Cincinnati, OH) announced the hiring of 

, PhD, RN, as Director, Regulatory and Scientific Affairs, and

, BS, PA, as Assistant Director, Medical and Scientific Affairs. 

 (Research Triangle Park, NC) announced the promotion of 

to Chief Operating Officer. In her new position, Pope will provide leadership and direction for the overall operations of the company, planning and coordinating the development of strategic objectives and goals. 

, a company in the development and marketing of drugs and medical devices, will use BioClinica's express electronic data capture system for multiple upcoming clinical trials. 

• The Clinical Data Interchange Standards Consortium 

(Austin, TX) announced the launch of the 

Coalition For Accelerating Standards and Therapies (CFAST),

 a follow-up to the partnership agreement signed earlier this year. 

 (Parsippany, NJ) has signed a collaboration agreement with 

, which operates as Blue Health Intelligence, to leverage HIC's secure healthcare claims database in IMS solutions, enabling biopharmaceutical organizations to advance the delivery of high-quality, cost-efficient care. 

will expand its current use of BioClinica's Express Electronic Data Capture solution to several upcoming trials. 

 (Fort Lauderdale, FL) announced a new enterprise agreement with the 

Consortium of Rheumatology Researchers of North America, Inc. (CORRONA)

 for the use of OmniComm's TrialMaster Suite

  of eClinical applications for all CORRONA registry studies. 

 (Miramar, FL) announced its recent designation as a 

 Prime Site, a distinction that gives Comprehensive an enhanced role in global clinical research and testing of new and more effective medicines. 

 (Malvern, PA) an enterprise consulting and eClinical products company, has established a systems integration partnership with 

, a provider of cloud-based business solutions for the global life sciences industry. 

(San Ramon and Los Altos, CA) announced a partnership with 

, a specialized clinical research organization conducting Phase I-IV studies for the pharmaceutical, biotechnology, and medical device industries. With this partnership, researchers can take advantage of each company's strengths by linking Nextrials' Prism

 , a clinical trial data management platform, with InClin's services to accelerate study starts and lower drug development costs. 

, (Hinckley, OH) a full-service contract research organization providing services for basic and applied research, clinical trials, and regulatory support, was awarded the prestigious NorthCoast 99 award for building and maintaining a great place to work in Northeast Ohio. 

 (Fort Lauderdale, FL) announced that its TrialMaster Study Data Tabulation Model Export Utility has been chosen by the Society of Clinical Data Management as a finalist for its 2012 Data Driven Innovation Award. 

(Winston-Salem, NC) announced that their eSource solution, SureSource, was recognized by The Society of Clinical Data Management as the winner of the 2012 Data Driven Innovation Award. 

, (Glen Burnie, MD) a company in patient enrollment solutions for the clinical research industry, announced the launch of its redesigned website 

. The new website aims to provide details for sponsor companies, CROs, and investigative sites who are seeking data on CSS's offerings and experience, including case studies, a creative portfolio, and a summary of services. 

 (King of Prussia, PA) released a site-level reference booklet that highlights qualifications, regulatory/EC, informed consent process, CIP compliance, resources, training, device accountability, documentation, and safety reporting for clinical research sites. 

 (Research Triangle Park, NC) ranks sixth in this year's InformationWeek 500, a list of the top technology innovators in the United States. The driving factor behind this year's InformationWeek 500 ranking was Quintiles' collaboration with Eli Lilly on an IT-enabled project to re-engineer the way clinical trials are planned and designed. 

 (Lincoln, NE) announced that it has been awarded full accreditation by the Association for the Accreditation Human Research Protection Programs (AAHRPP). Celerion's clinical facilities in Lincoln, NE; Neptune, NJ; and Phoenix, AZ, achieved this milestone. 

 (Chicago, IL and Ravensburg, Germany) reported that its Development Service doubled its revenues over the last five years, due to increased customer demand for support on complex biologics.  

 (King of Prussia, PA) has relocated its headquarters 1.5 miles from the original site in King of Prussia, PA, where the company has been located for the past 10 years. The new location will provide staff a spacious work environment and enhance the company's flexibility and capabilities to provide clinical research and development services for its clients. 

, (Philadelphia, PA) a global provider of health outcomes, announced the launch of a clinical research workflow technology designed to streamline data collection, analysis, and processing in clinical trials. The new offering, which comprises the EXPERT3 workflow platform and MyStudyPortal3 reporting engine, can simultaneously process health outcomes data across cardiac safety, clinical outcome assessment (COA/ePRO), and respiratory studies. 

 (Tucson, AZ) announced the availability of a new tool to help combat tuberculosis (TB)—a persistent disease resulting in 1.7 million deaths globally each year. The new tool—a standardized way to report research data—is critical for advancing new TB drug regimens. 

 (Titusville, NJ) announced the launch of JanssenMD, a new scientific resource for US healthcare professionals seeking instant access to current information about Janssen products marketed in the United States. 

Business News

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

Business and News Update November 2012

Act Insert cover

Pediatric legislation aims at letting children benefit more from pharmaceutical progress. The United States re-authorized it recently as FDASIA (FDA Safety & Innovation Act), the European Union one is in force since 2007. Drug developers have no choice anymore: they must consider children. Who could be against this? 

Clinical trials in children had a bad reputation. This has changed. The need to test new treatments is generally accepted; strong safeguards protect children's rights in research. Diseases that were a death sentence decades ago are chronic conditions today in adults and children (e.g., cystic fibrosis (CF) or insulin-dependent diabetes). Children with CF died young half a century ago; today their life expectancy is >40 years. Almost 90 percent of children with acute lymphatic leukemia (ALL) survive, but 10 percent don't. Survivors and non-survivors often go through two or more rounds of chemotherapy, a nightmare for patient and family. We need a breakthrough here. It will come. Are therapeutic breakthroughs achieved through pediatric legislation? No. Pediatric legislation promotes gradual improvements: earlier availability of new adult drugs, better dose calculation, and improved drug safety. Breakthroughs come from a mixture of science, dedication, and the market. Without entrepreneurs there are no new drugs. Human curiosity and science continuously challenge our traditional understanding. To reach patients, new inventions must reach the market. Companies do that, not academia. 

The medical market needs control to protect patients. Control should be balanced and not discourage innovation. US legislation balances mandatory requirements and incentives. EU emphasis is on mandatory requirements. The European Medicines Agency (EMA) will not register a new drug without a pediatric investigation plan (PIP) agreed with its pediatric committee (PDCO). PIPs should be submitted end of Phase I; their negotiation takes almost a year. The EU PIP procedure keeps many people busy: 66 PDCO members, 30 EMA pediatric coordinators and administrators; employees of 27 EU authorities; and people in industry, CROs, and consultancies. Even companies that develop drugs specifically for children must negotiate a PIP. The EU legislation originated in good intention; run by a bureaucracy with much power and little control, it starts to affect drug development. Companies will avoid therapeutic areas with extreme PDCO requests. Even the EU ombudsman criticizes EMA/PDCO for lack of transparency.  

Drug development is expensive. Frequent diseases are more and more treated by generics; research-based pharmaceutical industry is increasingly targeting rare diseases. FDASIA mandates a conference to accelerate development of products for pediatric rare diseases. The debate how to balance costs and how to prioritize will intensify.  

The more the societal framework allows the energy of parents, scientists, entrepreneurs, and clinicians to translate into new treatments, the faster breakthroughs will happen. Vision is a first step; there are many more steps until a new treatment reaches the market. It may begin with rocket science and/or common sense: a new receptor/antibody, a novel delivery device, a way to make research more child-friendly. We need a framework that facilitates, promotes, and rewards basic and applied research for adults and children. Blind trust into industry or academia or unlimited power to bureaucrats is not the right path. All institutions have hidden agendas. The debate will continue; at least we agree about the aim: better medicines, and children should benefit.

 Managing Director klausrose Consulting E-mail: 

A Closing Thought

A framework is needed to facilitate, promote, and reward basic and applied research for adults and children.

Pediatric Drug Development

As the CEO of PHT Corporation, a leading provider of electronic clinical outcome assessment (eCOA) and electronic patient reported outcome (ePRO) systems used in clinical research, I'm often asked what I believe have been the most important engines driving ePRO industry growth over the last decade or so. I've identified 10 key drivers, described here in reverse order of importance.  

The growth of electronic data collection (EDC) began about a dozen years ago. Companies using EDC studies for all data other than diaries, take three to nine months to lock the database. That's unacceptable—and why major pharmas always consider ePRO if they are using EDC and endpoints in patient or clinician outcomes. 

Two influential groups within the C-Path Institute have been major influencers: the Patient-Reported Outcome (PRO) Consortium, 

, and the Electronic Patient-Reported Outcome (ePRO) Consortium, 

. The PRO Consortium is significant because it is a collaboration with FDA, pharmaceutical companies, and ePRO providers. 

The ePRO Consortium is a group of ePRO providers that includes Almac, Bracket, CRF Health, ERT, ICON, and PHT. The consortium provides electronic technologies for trials capturing clinical outcome assessments as endpoints; and ensure that new instruments from the PRO Consortium are validated in various electronic formats.  

These two consortiums are working together to lower both the cost and the risk of using ePRO for all clinical research stakeholders.  

8: ePRO integration with objective measurement devices

The advent of objective medical devices such as the PEF meter for asthmatics and the glucometer for diabetics have been landmarks. Combining objective information from these devices with the subjective information gathered by electronic diaries significantly enriches what we call "the true voice of the patient."  

Patient non-compliance when using paper diaries has been outlined in a number of articles. One of these articles, published in the 

, notes that when doctors ask patients to recall recent health experiences such as pain and fatigue, "[patients'] recall is unreliable and rife with inaccuracies and biases." The problem is even more severe when patients use paper diaries.  

Concerns about the use of unsupervised paper diaries are justified. The FDA has taken note and expressed its concern in some of its guidances.  

6: Increase in the number of trials collecting PROs

The fact that the FDA, European Medicines Agency (EMA), and the Pharmaceuticals and Medical Devices Industry,  (Japan) are all interested not just in what physicians say but in how patients feel is driving more and more PRO-based labeling claims. Given today's regulatory and economic environment, sponsors are also focused on finding meaningful ways to differentiate their drugs. Having more information from patients helps.  

This report, written several years ago, notes that when sponsors migrate from paper to electronic data capture, the change can be categorized as minor, moderate, or substantial. The degree of change requires different types of validation. Because the report provides pragmatic guidance for PRO scientists to follow when migrating from paper instruments to electronic ones, it has speeded the adoption of ePRO. 

4: Improved site and sponsor satisfaction

Many of us remember the days when ePRO was new and didn't work as well as it does today. As sponsors gained experience—particularly large pharmas looking for competitive advantage—ePRO site and sponsor satisfaction improved and adoption increased.  

The Merck insomnia study showed the significant return on investment ePRO delivers.  

The trial was executed to help Merck better understand the scientific and business benefits of ePRO versus paper for trials with patient-driven endpoints. The trial was designed so that an already-approved drug was used and patients were randomized; using both paper and electronic arms. Merck deduced that they could have 56% fewer patients using electronic data gathering and achieve exactly the same study power.  

Similar reduction in data variance in trials using electronic diaries versus paper diaries has been published in other indications, including urinary incontinence, asthma, and chronic constipation, and concretely demonstrates the significant ROI ePRO delivers. 

2: PRO guidance and other regulatory documents

The FDA PRO guidance covers the importance of PROs and clinical outcome assessments in research as well as the importance and benefits of implementing measures electronically. The same material is covered in the EMA reflection paper on health-related quality of life about collecting data electronically. These documents, as well as the eSource draft guidance documents, 

http://www.fda.gov/downloads/Drugs/.../Guidances/UCM239052.pdf

, that came up earlier this year, all strongly support electronic data capture.  

All these guidelines demonstrate that regulators now expect to see the use of electronic systems rather than paper methods to collect clinical outcomes.  

The number one driver of ePRO: smartphones and the proliferation of consumer technologies. The PHT ePRO/eCOA system collects data on smartphones, with great success.  

is the President and Chief Executive Officer of PHT Corporation, 500 Rutherford Avenue, Boston, MA, e-mail: 

Patient Reported Outcomes

A countdown of the top 10 developments that have most influenced the ePRO industry over the past decade.

ePRO Industry Growth

In late August, the FDA elevated the Office of Generic Drugs to report directly to Janet Woodcock, the director of CDER. The move reflects that segment of the industry's importance in CDER. Specifically, that almost 80 percent of all prescriptions in the United States are now for generics.  

On the heels of that announcement, FDA announced in early October that it had discovered budeprion XL 300 mg, manufactured by Impax (marketed by Teva) was not therapeutically equivalent to the reference drug 

. That drug is Wellbutrin 300 mg, which is prescribed for major depressive disorder and for the prevention of seasonal affective disorder. Impax chose to withdraw the drug from the market. No other Wellbutrin XL 300-mg generics were involved.  

The determination of bioequivalence for the 300-mg dose was actually never studied by Impax, and waived by FDA based on safety reasons when the generic was approved in December 2006. Rather, the data from the 150-mg dose was extrapolated and used for its approval for bioequivalency because it was determined testing the higher dose could cause seizures in healthy volunteers. 

The FDA notes in its announcement that it received 85 postmarketing reports of adverse events or lack of an effect after patients switched from Wellbutrin to the budepiron between January and June 2007. However, the FDA said, "Reports of lack of effect were difficult to interpret given the natural course of depression in the treated population." In November 2007, the FDA asked Impax/Teva to conduct a bioequivalence study to compare the two drugs and doses, however, it was terminated in late 2011 by Impax/Teva because it could not meet the recruitment numbers.  

In 2010, FDA decided to conduct its own direct bioequivalent study, with results available in August 2012. In the report, it asks "Why did it take FDA two years to complete the bioequivalence study?" The answer? One that should be familiar to most clinical trials professionals: "FDA worked to get funding for the study, designed the study, obtained approval from the Institutional Review Board for Protection of Human Subjects, recruited and enrolled healthy volunteers, conducted the study, developed an analytical method of analyzing the data, and completed its analysis of the study data." 

So while the office is elevated, and under Generic Drug User Fee Amendments of 2012, FDA will receive $1.58 billion from generic drugmakers that were previously exempt, this is the first sticky situation involving a generic drug since the move. Prior to that the Associated Press reported that the FDA has only reversed approval on the equivalence of three drugs in the last five years.  

And while this Wellbutrin issue came out during the same time as the meningitis outbreak and compounding issue, which had significant mainstream media coverage, this generic issue could have downstream effects with consumers. Specifically, FDA's consumer information about generics on its website—Figure 1 clearly states that the generic has the same quality and performance as the brand. And that they must be equivalent to the brand. On average the generic version costs 80 percent to 85 percent less than the branded version (Figure 2). 

According to the FDA's information for consumers on biosimilars, they are not generic versions of biological products. "The word 'generic' applies only to small-molecule drugs that are the same as, and bioequivalent to, an already-approved small-molecule drug regulated under the FD&C Act." Biosimilars rather are 'highly similar' to the reference biological product."  

Apparently, FDA or CDER needs to spread the word on biosimilars. According to a recent report from Industry Standard Research, titled "Improving Patient Recruitment in Biosimilar Trials," (

http://www.isrreports.com/industry-reports/improving-patient-recruitment-in-biosimilar-trials

)survey respondents from investigative sites, roughly half are not familiar with biosimilars. However, they would be excited if a biosimilar protocol came across their desk. In addition, the ISR Report noted that the surveyed sites have conducted 19 studies in the past 24 months, and of those studies, five or six has been for a generic product, and one for a biosimilar. 

News

In late August, the FDA elevated the Office of Generic Drugs to report directly to Janet Woodcock, the director of CDER.

Generic Drugs Making Waves

Data correction rates are indicative of the overall quality of data during a clinical trial. A higher rate of data correction would indicate a lower quality of data being entered, which raises concerns over the accuracy of data being collected during the study,and also, the level of training of the site personnel with electronic data capture (EDC) systems or other aspects of the protocol. The training and comfort level site personnel have with EDC systems would also contribute toward timely entry of data during the conduct of the study. A longer duration of time between subject visits to actual entry into the EDC would delay important decisions that determine the course of the study and may even indirectly impact patient safety. 

This month's Insights graph provides a comparative—and contextual—evaluation of trends in terms of data correction rates and the time from subject visit to eCRF entry. This data is derived from Phase II and III studies in the Medidata Insights metrics warehouse for the time period between 2007 and 2012. As evident from the graph, the data correction rate remains essentially flat while visit to data entry has a downward trend, with an almost 80% decrease during the time period.  This clearly indicates that timely data entry does not necessarily translate to high initial data accuracy. 

Interestingly, data correction rates also decreased 21% in 2012, from an all-time high at 6.6% in 2007.  It remains to be seen if this downward shift in 2012 would usher a downward trend in the years to come. It is possible that any shift in data correction rates due to timely entry of data (as suggested by the downward trend), is masked by other factors such as increases in the complexity of both eCRFs and protocols. A decreasing trend in data entry time is an indicator of better overall use of EDC systems, which can be used to relay insightful information, during the course of a clinical trial. It also highlights the potential opportunity of business analytics solutions, which seamlessly gather data from EDC and other eClinical systems to serve as key drivers for better planning and monitoring of clinical trials.  

What other factors do you think are impacting data correction rates? As always, Medidata is interested to hear your take on this result. Please stay tuned as the company delves further into the Insights metric data through 2012. 

In the Race to Capture Clinical Data, Does Data Quality Suffer?

Topline revenue reports from global investigative sites show that they have rebounded from a dismal 2010. Average per site revenue levels in 2011 were up nearly 6% over the prior year. A closer look, however, reveals a community overloading its capacity and reluctant to take on additional infrastructure as clinical trial activity increases. Nowhere is this more evident than among study coordinators, long regarded as essential personnel managing day-to-day responsibilities at the clinical site.  

A recent study conducted by CenterWatch documents a critical workforce that has seen its workload and responsibilities increase dramatically during the past several years while salary levels have remained flat when adjusted for inflation. Yet, despite the higher workload, the turnover rate among clinical research coordinators (CRC) has dropped far below historical levels seen during the past decade. 

Given these mixed dynamics, sponsors, CROs, principal investigators, and site directors need to proactively monitor and manage this currently stable work force to ensure that experienced and motivated capacity remain in place and productive as global clinical trial activity and workload continues to rise.  

The study was conducted online and e-mailed to approximately 12,000 study coordinators worldwide during August and September 2012. A total of 269 professionals from independent research centers, private physician practices, academic institutions, and hospitals responded to the survey. Half of respondents work in for-profit investigative sites while the other half work for academic medical centers or government-funded hospitals. An average of three full-time study coordinators are employed by each site, and the vast majority of sites (93%) also employ part-time study coordinators.  

The CRC's workload is quite full and varied: Study coordinators report spending the greatest proportion of their time on administering study protocol requirements. Other top areas of time commitment include collecting and maintaining clinical data; overseeing patient recruitment and retention activity; ensuring GCP-ICH compliance; maintaining quality assurance; serving as the primary contact with sponsors, CROs, and regulatory authorities; reporting adverse events; and managing queries. 

Workload—as measured by the number of clinical trials actively managed by each CRC—has increased 7% annually over the past 10 years. The median number of studies managed by a study coordinator on an annual basis jumped from 4.3 in 2001 to 7 last year—based on anecdotal reports from sites—and is expected to be even higher in 2012. The typical coordinator personally oversees an average of 80 patients on an annual basis. 

Figure 1. Median annual  studies per CRC are steadily on the rise.			

In addition to increased workload, study coordinators report that the typical clinical trial has become far more complicated and demanding. Regulatory requirements—particularly paperwork associated with GCP-ICH compliance—have intensified. Study coordinators note that documentation and other tasks formerly completed by study monitors have been relegated to CRCs and other site staff. Protocol complexity has increased the amount of administrative work and made it more difficult to recruit patients. CRCs also report that sponsors have added an increasing amount of training to familiarize coordinators with new assessments, procedures, and IT systems.  

If that weren't enough, coordinators also note than when other staff positions have been eliminated at the site, CRCs are required to take over these tasks including marketing, business development, and managing financial matters.  

While workload has grown substantially, CRC salary levels have remained flat—when adjusted for inflation—during the past decade. And nearly 8-out-of-ten (78%) CRCs believe that their salaries are no longer commensurate with the amount of work they perform. A third of CRCs believe that higher workload demands impact their ability to complete tasks and do their job well. 

Figure 2. CRCs are increasingly dissatisfied with their salaries.			

Although salary levels are misaligned with workload, turnover rates among CRCs are the lowest they've been in a long time. In 2002, 56% of study coordinators had been in their positions for less than three years; this year, almost half of survey respondents had been in their current job for at least seven years. A total of 72% of respondents have been in their current positions for at least four years; in 2002, only 44% of study coordinators stayed in their positions for more than four years. 

The CenterWatch study also found that more experienced CRCs tend to stay with their employer longer than those with less experience. Almost three-fourths of study coordinators with at least nine years of clinical research experience have been in their current position for seven or more years. 

Study coordinators are staying in their positions longer, in part, because the economy has made it difficult to change jobs. Yet the study results also suggest that longevity has improved for the simple reason that a high proportion of study monitors like their job. In particular, study coordinators enjoy working with patients and find it gratifying to participate in studies of investigational treatments. CRCs also enjoy the collegial site culture. When asked to rate the biggest benefits of their job, nearly 43% of survey respondents said they found the work was interesting and satisfying. About 20% indicated that working with patients was the best part of their job. Nearly 15% said they liked the flexibility and autonomy offered by the position. 

Principal investigators and site directors recognize and appreciate that experienced study coordinators can be a competitive advantage. During the feasibility process, sponsor companies routinely ask investigators about their study coordinator's level of experience and number of years at the site. 

Although investigative sites report that they cannot increase CRC salaries because of budget constraints, successful sites find other ways to make their study coordinators feel valued and to make the job meaningful for them. About 70% of sites typically pay for at least part of the cost of continuing education credits for their study coordinators. Other sites look to ease CRC workload by having other staff help with data entry, regulatory responsibilities, or scheduling patients.  

In the 2012 study, however, nearly a quarter of study coordinators feel that they lack opportunities for upward mobility at their site. The vast majority —92%—of study coordinators report that they want to advance their careers and, as the economy improves, many report being open to new opportunities. Most sought after career aspirations include becoming a study monitor (26%), a project manager at a CRO or sponsor company (16%), or a site manager (16%).  

Simplifying protocol designs—a responsibility that rests with the sponsor—would go far in providing relief for site personnel, especially study coordinators. Today's protocols have an average of 170 total procedures administered over 11 visits during a 175-day period. Studies conducted by the Tufts Center for the Study of Drug Development have consistently demonstrated a strong inverse relationship between protocol complexity and clinical trial performance: The higher the level of complexity, the longer the study will take and the harder it will be to recruit and retain study volunteers. Many sponsors are now reviewing their protocol design practices to identify improvement opportunities that will both ease execution burden and improve study efficiency and speed.  

Study coordinators frequently ask to provide feedback on study feasibility early in the process and provide logistical input before a study begins. Active solicitation of CRC feedback and the application of these suggestions when appropriate may also ease coordinator workload. 

Sponsors and CROs are also working to form stronger relationships with their site partners. Some of these relationships are designed to offer some relief to CRCs: Both Quintiles and Covance have programs, for example, that provide dedicated liaisons and support teams that can offer practical assistance to site personnel having trouble with administrative tasks, patient recruitment management, and slow study initiation.  

At the moment, the study coordinator workforce remains stable. Yet sponsors, CROs, and investigative site management face significant challenges if experienced and productive study coordinators, exhausted by an ever-increasing workload, begin to exit their sites in order to earn higher salaries and advance their careers. The CRC operating environment is reaching a tipping point and must be monitored and managed proactively.

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

CTI Insights

Study coordinators see responsibilities increase dramatically while salary levels remain flat.

Are CRCs Reaching Their Tipping Point?

A mid-year summary of the European Medicines Agency's 2012 activities underlines the growing trend toward closer collaboration between international regulators. 

EMA has appointed a new FDA liaison officer, based at the FDA, and this move is part of the overall plan to promote EMA-FDA interaction on specific issues. Both agencies acknowledge the importance of starting dialogue early in the development process and promoting a high level of informal interactions between EMA and FDA and exchanges on ongoing applications. EMA has also appointed a new Japanese liaison official. 

 Guido Rasi is the EMA's Executive Director.			

"The agency provided support to the European Commission for collaboration with Russia on GCP," noted the authors of the report. "As part of the pilot program for the parallel assessment between EMA and US FDA of quality by design aspects in marketing applications, a parallel evaluation in a first submission has been completed. Harmonization of lists of questions has been undertaken." 

On a less positive note, however, the report reveals that public access to clinical trial results is delayed, pending the launch of the database. Moreover, the discharge by the European Parliament for the EMA's 2010 budget has been delayed. The Parliament requested improvements in a number of areas, particularly in managing conflicts of interest. EMA has now published declarations of interests, and the CVs of all managers have been included in the European expert database. EMA expects the issue to be resolved by the fourth quarter of 2012. 

"Our main performance indicators have been met. The mid-year report indicates that the agency is on target to meet its core business objectives for 2012," Executive Director Guido Rasi told the EMA's Management Board on October 4. Among the other highlights in the report were: 					

The number of new marketing authorization applications for new human medicines received so far is largely in line with 2011 figures for the same period (52). But the forecast for applications to be submitted by the end of the year has fallen from 112 to 101, owing mainly to a lower than expected rate of submission of applications for generic products for human use.

Requests for scientific advice and protocol assistance for new human medicines rose by almost 14% and 24% respectively compared to figures from the same period in 2011. This confirms the growing importance of early regulatory advice on development programs, according to EMA.

There was a significant increase in the number of applications for orphan designation (30% above the same period in 2011). About 63% of the orphan medicinal products fund had been used (€3.79 million of €6 million). Overall, EMA's budget for this year is 222.5 million euros, of which 71% (€158.1 million) had been committed by the end of the first half of the year.

The plan to move the Agency to new premises (Project 2014) is progressing in line with expectations.

The number of face-to-face meetings involving EMA staff continues to fall. There were 221 such meetings in the first half of 2012, compared with 287 in the same period of 2011, and 316 in the same period of 2010. The number of virtual meetings is growing, however.

EMA currently has 559 temporary agents, 113.5 contract agents, and 93 other staff (national experts, interims, trainees).

For clinical and non-clinical compliance, EMA received 42 GCP inspection requests, of which eight were pharmacovigilance inspections. No good laboratory practice inspection requests were received. In April, the agency published a reflection paper on GCP and ethical aspects of clinical trials conducted outside of the European Union.

A successful link was made between the EU Clinical Trials Register information and the World Health Organization's International Clinical Trial Registry Platform.

Implementation of the new pharmacovigilance legislation is progressing as planned, according to the report. EudraVigilance aggregated data for centrally authorized medicines for human use was published on May 31, 2012. Since the Management Board's last meeting in June 2012, the Pharmacovigilance Risk Assessment Committee has been established and met three times. The board has pledged to continue to monitor the implementation of the legislation carefully. 

A mid-year summary of the European Medicines Agency's 2012 activities underlines the growing trend toward closer collaboration between international regulators.

EMA's Mid-Year Report Merits Scrutiny

Development of clinical outcomes assessments (COAs) for use in multinational clinical trials requires thorough assessment of readability and translatability of the source. A highly translatable source will facilitate the achievement of conceptual equivalence during linguistic validation, resulting in valid data pooling across languages. Several issues should be considered in an effort to eliminate translation difficulty during harmonization and cognitive debriefing. Instrument developers should collaborate with the language service provider (LSP), and complete a translatability assessment prior to linguistic validation.  

When developing COAs for multinational trials, several key steps can serve to ensure ease of translatability and achievement of conceptual equivalence across languages. The LSP should review a draft of the COA to identify any potential translatability and readability concerns. This "face validity" review serves to pinpoint problematic phrasing and concepts and to make suggestions for revision prior to translation. Common problems identified may include conceptual overlap in response sets, unbalanced response sets, ambiguous key concepts, idiomatic items for which direct equivalents may not exist across languages, incomplete instructions and double-barreled questions in which a single question seeks to measure multiple constructs. Identifying and addressing such issues early in development saves time and unnecessary expense. The LSP may also make recommendations for minimizing respondent burden. A Flesch-Kincaid readability test can be applied and revisions suggested to improve comprehension by a broad target population. A recent COA face validity assessment required that the questionnaire be taken from grade level 17 to grade level 8. Successful revision was accomplished by simplifying instructions and terminology, defining medical terms, and providing examples of complex concepts.  

Following the face validity review and instrument revision, a translatability assessment should be completed. This review is carried out by linguists within desired language groups to identify translatability concerns within and across languages and to recommend source revisions to improve translatability. An important outcome of this assessment is to identify items that are so culturally-specific that they would potentially yield differing interpretations across languages. According to the "ISPOR Patient-Reported Outcomes Translation and Linguistic Validation Good Research Practices Task Force Report,"

  in order to pool data from multi-country studies, cognitive equivalence of PRO measurement concepts should be established. A translatability assessment will identify idiomatic phrasing, ambiguous concepts, and other areas of a COA with the potential for problematic translation. Though idiomatic phrases such as 

 can create difficulty in finding equivalent concepts when translated, equivalence is achievable through completion of linguistic validation but may require more rounds of revision during harmonization.

Recent research has revealed ways in which the translatability of COAs can be improved. A popular concept found in patient questionnaires, 

, has recently been shown to hinder data validity. The ambiguous nature of 

 results in multiple interpretations across languages. For example, German respondents interpret the concept as something that is a 

 to Russian speaking respondents. These discrepancies present a problem for data pooling across languages. Alternatively, it is recommended that the concepts for measurement be specifically defined. For example, instead of asking a patient how much psoriasis 

 him or her, it would be best to ask how 

one's psoriasis has been. Using these alternatives increases the likelihood that what is intended for measurement is actually being measured because the variation in interpretation of the concepts is much less likely. Analysis of the translatability of 

 has also shown that more specific concepts, such as 

 will yield greater conceptual equivalency when translated. Replacement of ambiguous concepts with more specific concepts will better measure what researchers are intending to measure.

Research exploring the translatability of response sets was conducted by Gawlicki, et al. 2012 to determine optimal response sets for patient questionnaires for which a high degree of translatability is vital. A popular response set measuring symptom severity or frequency is 

not at all, a little bit, somewhat, quite a bit,

 In observed translations, the ambiguities in this response set will cause conceptual overlap when translated, as reported by linguists participating in the study. Furthermore, the concept of 

 is often omitted as it does not exist in many languages. A response set observed to have a high degree of translatability and no issues with conceptual overlap when translated is 

 These terms render this response set more specific and generally will result in a more sound translation. Results from the study showed that a maximum of five response options will help prevent concept overlap in translation. If more than five response options in a set are desired, either a 

Creating a COA for use in multinational trials requires careful review and consideration during the instrument development phase. The aforementioned steps are recommended in order to yield the sound translations necessary for later pooling of data. 

1. D. Wild, et al., "Multinational Trial—Recommendations on the Translations Required, Approaches to Using the Same Language in Different Countries, and the Approaches to Support Pooling the Data," Value in Health, 12 (4) 430-440 (2009). 

2. M. Gawlicki, B. Brandt, S. McKown, M. Talbert, "Achievement of Cultural Equivalency when Translating a Patient-Reported Outcomes Instrument Containing English-US Idioms and Colloquialisms," poster presented at the ISPOR 17th Annual Meeting; (June 2-6, 2012). 

3. M. Gawlicki, B. Brandt, S. McKown, M. Talbert, "Application of the Bother Concept Across Cultures," poster presented at the ISOQOL 18th Annual Conference (October 26-29, 2011).  

Recommendations for assessing translatability.

Applied Clinical Trials-11-01-2012

Taking the Pulse of Ethics Committee Views

Act Cover

Survey Results of Start-Up Cycle Times

Business and News Update November 2012

Act Insert cover

Pediatric Drug Development

ePRO Industry Growth

Generic Drugs Making Waves

In the Race to Capture Clinical Data, Does Data Quality Suffer?

Are CRCs Reaching Their Tipping Point?

EMA's Mid-Year Report Merits Scrutiny

The Local Touch

Capturing Suicidal Patient Data

Regulators, Sponsors Seek to Streamline Research

Social Media Recruitment

Applied Clinical Trials Digital Edition - November 2012