Nobody will really doubt the successful use of EDC solutions in clinical research worldwide. The technical realities are mostly given, Internet is available everywhere, and nearly all parties in this field are able to use the Web. However, what will be the factor of EDC success for the future? What's the reason that using EDC today is not as successful as a lot of people thought it would be at this point years ago?

There are a lot of reasons for the successful or unsuccessful use of software solutions. Is the problem sitting before the computer or inside the system? Let's look at the different user groups of EDC solutions and each of their specific requirements.

The core business of the user at a site isn't entering data into a computer. A good EDC solution has to optimize economical aspects and help fulfill the study specific and general requirements. The following are some aspects that should be taken into account when rating an EDC system.

The design of the system has to follow the same steps the investigator has to work during the visits. It has to support the planned workflow. If a check violation or a discrepancy to the protocol is given, the system has to provide a message that helps the user identify the reason for this.

With implementation of EDC, many investigators had the impression they were a kind of outsourced data entry personnel. This shouldn't be. The process of data entry should be optimized so that the mounds of data should get entered automatically (e.g., by uploading data in an eDiary and having it entered using automatic processes).

Another important issue is password management. One of the most frequent reasons to call the help desk is because the user has forgotten a personal password. An optimized automatic password managing process can help to minimize the need of a help desk and minimize idle time if there is a password problem.

Experience has shown that many users were not able to admit their problems in working with a new EDC system. The effects are shakiness and sometimes fear of contact with the system. To anticipate this, all users should be trained well and have the opportunity to test the system as an exercise application without any risk.

Also, all sites should have enough user accounts with separate authorities for the different roles at the site, including study nurse, investigator, and site leader.

A monitor should have experience in using an EDC solution. The main focus of this user group is the entered data and its status and quality.

The monitor has to identify all data and information the investigator confirmed before. For this group, it's very important to see what's going on and know where the data that needs to be reviewed is. Optimally, the source data also is available in the application (e.g., by using digital pens and dotforms technology).

Another way to minimize the amount of work is to use automatic processes, such as uploading large data volumes or using other available techniques for data transfer. Online query management and resolution of discrepancies and violations is another very important process that should be accomplished easily.

The help desk should be familiar with the system. Their main focus is identifying timely problems a user may have (e.g., access problems). An automatic generated notification to the helpdesk or a new user password helps to minimize duration of waiting for updated EDC access.

To see what's going on in the EDC system, a kind of user management system with different views of user activities helps to provide a good overview and feeling about the ongoing processes. If any questions are identified as important for other users, these should be documented within a FAQ database within the EDC system.

Last but not least, all study relevant documents have to be available for download as actual and old versions. This allows all users to be aware of and to find complete and necessary information.

Data management is interested in high data quality and therefore they specify all checks they need to achieve this target. This user group also is interested in having an adequate overview about the quality and status of entered data.

If available data and information is not documented and is needed, data management must have the opportunity to create queries. Special online available reports supported within the EDC system can give an optimal status report and feedback about the ongoing processes of the study and the quality of EDC specification (checks, messages, etc.).

Automatically generated notification emails by documented adverse events, serious adverse events, or subject pregnancy optimize the processes to react if required. If an amendment of the study plan is needed, the system must be able to manage the changes easily.

The sponsor is interested in all information that helps to review the progress of the study and managing all parties. Therefore, they also need online access to view entered data for review and controlling, as well as online reports for status overview of active sites, subjects/subject status, queries/query solution, and completion of documentations. These reports are also important for the payment process and to confirm the work performed by the user.

These issues should be kept in mind when planning a new study to optimize the quality of EDC solutions. Definitely, there are a number of further issues that have to be borne in mind, regardless of the data capture process that will be used.

 For the eCRF, it's extremely helpful to support the normal workflow at the site. During the investigation, the user—the study nurse and investigator—should follow the eCRF page by page. All values that are not available at the moment should be part of a separate section that can be entered later. If a number of data is available as an electronic file (such as lab data), the acceptance of the eCRF will improve significantly if this data is not manually entered. There are a number of opportunities available to do this automatically.

Consider that this phase is much more time consuming than for a paper CRF because you have to design the whole process of study execution.

 Depending on the expected know-how at the sites, the given information at each eCRF page and for each check violation has to be optimized. A professional research institute can operate with a more complicated design than a "standard" medical practitioner. Depending on their experience and know-how, the integration of checks has to be adequate for the requirement of data quality and practical for the user.

Set up the EDC system and check the planned workflow and data entry views for practicability. Especially necessary: The implemented checks should be tested from the point of view of the investigator. This user group should be able to understand each check violation to enter the needed data and information.

All users should be trained personally or by phone to handle the EDC system. When training, the main focus should be the general function of the system and workflow and the study specific extras or requirements. For the launch period, an exercise version of the EDC solution should be available so that users can try to handle the system without any real risk of affecting the study. This kind of use is less stressful for the user.

Additionally, all needed documents in the actual version should be provided within the system.

 Real-time monitoring to identify any open issues that have to be clarified is helpful, especially with documentation of the first patients. This is the point of time to give support for an optimal start. During the study, it's good to have a prompt query process.

 For effective study management, controlling a number of real-time reports is absolutely essential. The clinical study coordinator has to use these instruments to optimize the ongoing process and to motivate all participants by supporting them with actual achieved milestones and operating figures within a monthly status report.

To bear in mind these different requirements and the different operating experiences, some reasons of the past or existing problems get clearer. Most EDC systems appear to be developed from a data manager or people with a data management background. Understanding the requirements of all user groups that have to work with and not against the EDC solution is the key success factor for each system. Therefore it could be very helpful to discuss the draft EDC solution with different groups of EDC users to identify possible problems of the design. Use the feedback and optimize the EDC solution before starting the study.

And don't forget: Each study has its own requirements. Think about all the requirements before setting up an EDC solution, otherwise you'll have to find resolutions for problems caused by the EDC system. Be sure to identify the operating experience of the user who will work with the EDC solution and try to support them as much as possible.

 is managing director for Amedon GmbH, Willy-Brandt-Allee 31 c, 23554 Lübeck, Germany, email: 

Articles

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Putting a Face on EDC

http://appliedclinicaltrialsonline.findpharma.com/appliedclinicaltrials/CRO%2FSponsor+Articles/Preapproval-Opportunities/ArticleStandard/Article/detail/522052?contextCategoryId=44942&searchString=patient%20organizations

2.) Mission Possible: Rebranding Clinical Research

http://appliedclinicaltrialsonline.findpharma.com/appliedclinicaltrials/article/articleDetail.jsp?id=416537&sk=&date=&pageID=3&searchString=patient%20organizations

3.) Recruitment Strategies: A European Perspective

http://appliedclinicaltrialsonline.findpharma.com/appliedclinicaltrials/article/articleDetail.jsp?id=306615&sk=&date=&%0A%09%09%09&pageID=4&searchString=patient%20organizations

The essential role that patient organizations can play in the research process, particularly in clinical trials, is often overlooked. The last four decades show not only a steady growth of the number of patient organizations but also an increasing interest in the research process and drug development. 

Nowadays, patient organizations can offer traditional, scientific research additional knowledge. Knowledge that is derived from the practices and experiences from the patient organizations. 

The combination of traditional, scientific knowledge (evidence based) with the practice based-knowledge from patient organizations creates an added value. This added value can play an important role in the development of clinical trials. 

Several examples of this added value will be mentioned in this article. Furthermore, the article explores the differences between patients, consumers, and clinical trial participants. 

There is a large difference between consumers as incidental users of health care and patients who are more or less constant users of health care services. The citizens of our society in their role of consumers are mostly interested in minimizing their health care insurance costs. These same citizens in their role as patient are more interested in questions such as where do I find the best doctor? The best hospital? And the best treatment or medication for my disease? 

As a consequence, patient groups stand more alongside the research community, acting as a critical friend and as part of the process to find solutions for unmet medical needs. On the contrary, consumer organizations take a more confrontational stance, stressing the risks, dangers, and problems of medical research. 

The difference between consumers and patients is also relevant when answering the question: Who is the trial participant? 

The trial participant can be a healthy volunteer who is getting paid for their cooperation. The trial participant can also be a consumer, who all of a sudden gets ill and at the time of the diagnosis will be asked to participate in a trial with relatively little background knowledge. And in regard to providing informed consent, has had little or no time to think about the decision. The trial participant can also be a patient, partially organized in a patient group or aware that there is a patient group and has some background knowledge of the condition and respective treatment options. 

Trial participants are seldom organized, nor have contacts with patient or consumer groups. Trial participants are represented in research ethics committees (EC) by laypersons, and these laypersons also have almost no contacts with trial participants and patient or consumer groups. 

For most clinical research organizations, investigators, and pharma companies, it's not easy to contact potential trial participants if they're not organized in patient groups. 

Where in the past, patient organizations focused on their three traditional roles—education/information, peer support, and advocacy—they now play a fourth role: consultant and participant in scientific research and related policy issues. 

The story of Patrick and Sharon Terry [see sidebar] is an example. Another example is EULAR (European League Against Rheumatism) and OMERACT (Outcome Measurement in Rheumatology Clinical Trials). A traditional endpoint in clinical research for rheumatoid arthritis was pain. Input from patient groups resulted in the formulation of two new endpoints: fatigue and sleeplessness.

This development illustrates how patient organizations can provide clinical research with additional knowledge, which translates into additional value. 

The involvement of patient organizations comes at a time when a new paradigm for the clinical trial process is needed. Sir Michael Rawlins of NICE  described it as inefficient, outdated, slow, and expensive.

There are several reasons to go for a new paradigm: the increasing costs and time needed to conduct a clinical trial; a lack of patients for clinical trials in several disease areas; and a lack of knowledge and awareness in society about the need for clinical trials. 

To the statement of Rawlins can be added the outcome of the recent European Commission–EMEA conference,  "The Operation of the EU Clinical Trials Directive (Directive 2001/20/EC) and Perspectives for the Future," which officially confirmed earlier anecdotal doubts about the fact that the EU rules don't work properly.

  More recently on December 1, 2008, in Brussels the results of the ICREL (Impact on Clinical Research of European Legislation) survey were discussed. These results also confirmed the outcome of the 2007 European Commission-EMEA conference. ICREL's aim is to measure and analyze the direct and indirect impact of the Clinical Trials Directive 2001/20/EC and related legislations in the EU on all categories of clinical research and on the different stakeholders: commercial and noncommercial sponsors, ethics committees, and competent authorities.

Several patient groups also expressed their concerns about the EU Clinical Trials Directive and asked for more involvement of patient organizations in the clinical trial process, especially participation of patient groups in research ECs. Early, active involvement of patient organizations in clinical trials will not only contribute to therapies that are better adapted to the needs of patients but will also contribute to the cost effectiveness of clinical trials and health care in general. 

Thus, the need for involving patients not only as subjects but also as partners in investigator and industry trials originates from patient organizations and from other stakeholders in clinical research. In addition, there are societal changes stimulating new inter-stakeholder relationships in this area, with patient emancipation making patient–doctor relations increasingly equal instead of paternalistic. 

Patient organizations represent the patient's needs, views, and perspective. In addition to their better known role in the informational and psychosocial support area, patient organizations increasingly realize the value of their expertise for biomedical research. As a result, patient organizations are increasingly willing to contribute to the drug and therapy development process, especially in serious disease areas without either adequate care or stabilization of symptoms. Patient involvement is not only limited to biomedical research but also exists in the development process of medical treatment guidelines and standards of care. 

The closer involvement of patient organization representatives can also be expected to add value to the clinical trial process. This added value could, for example, manifest itself in clearer formulation of written patient information material such as the informed consent form; the debate over whether or not a particular type of research is stressful for a given patient group; the question of whether or not the required number of trial subjects is achievable; and the debate over whether or not a particular type of research ought to be suspended in the event problems arise. 

Patient organizations can also be asked by the research ECs for their opinion in cases where research that directly concerns them is on the agenda. In those cases where this type of dialogue does not take place, patient organizations will be less willing to accept the decisions of the ECs. 

As a result, this can delay the process when researchers or ECs overlook practical problems for patients to participate. There is also the possibility that when suggestions from patient groups are accepted, the new research proposal will have to be seen again by the EC, causing delays. 

It is unrealistic to expect that the process of involving patient organizations in the clinical trial process can happen overnight, but it does seem sensible to reflect on this involvement and to embark on a dialogue. Patient organizations will have work to do on this process also. They must learn to look beyond the problems that are specific to their own particular disease, which will require a certain amount of skills and background knowledge. 

To work on this, the European Network of Patients Partnering for Clinical Research was recently established to identify the needs for patients partnering in clinical research. They formulated a PatientPartner project that has just received a substantial FP7-grant from the European Commission to work on these issues. 

 This project is being done by key European and national patient network organizations under the umbrella of European Genetic Alliances Network (EGAN) and the European Forum for Good Clinical Practice (EFGCP). 

The PatientPartner project is an indication that European patient groups are on their way to play their part in the clinical trial process. Certainly this will lead to the identification of problems that have to be solved by them or by acting together with policymakers and regulators.

  Among the future problems and action steps that can now be identified are:  

 The potency of patient organizations in the different phases of clinical research is not clear and not used. An example is the adjudication of risk and benefit. Certainly with incurable diseases, there is little likelihood of a direct benefit to the participant. However, the hope of a benefit is perhaps a significant driver for those affected. 

How can research using patients put this into the right context? How acceptable is it to offset societal benefits against individual risks, and is there a case for allowing greater level of risks to be tolerated if the benefits to society are potentially large? Does understanding of risks change patient behavior and if so, how? Is the notion of altruism really a factor in individual decision making? And do the answers to these questions change if children are involved? 

 There is a big gap between the increasing willingness of patient organizations to participate in the different aspects of clinical trials and the legal room that exists to really fulfill that role. The added value of the involvement of patient organizations in the governance of clinical trials is either not clear or not used at the respective levels of the EU (guidelines, directives, regulations), their different member states (national legislation) and the trial level (organization, coordination). 

For patient organizations, it is important to understand the interests and the driving forces of the other stakeholders, the constraints exercised on public and private sector researchers and clinicians, and the regulatory and policy frameworks in which they have to operate. Mutual understanding between these stakeholders will improve the quality of the research, but structural dialogue between patient groups and the other stakeholders is still in its infancy. 

 Patient groups are urgently needed in specific areas of ethical and organizational complexity. It is not yet clear how patient groups can fulfill this role, for instance, in the case of pediatric research and in the availability of patient registries, clinical data banking, and biobanking. Pediatric research is particularly sensitive because of the potential for exploitation of vulnerable minors unable to give informed consent. Yet without this research childhood diseases will remain poorly treatable. 

Feature Article

Advancing medicine and the clinical research process with the help of patient organizations

Patient Power

A main theme of health reform is to make health care cost and quality information more transparent to better inform treatment decisions by providers and patients. Policy analysts consider a lack of transparency in health care financing a serious problem for the nation's health care system. 

Expanded use of health information technology by providers promises to uncover information on provider quality and costs and communicate it to the public. And objective comparisons of treatment effects would supplement the basic safety and efficacy data developed by sponsors to support market approval of products by the FDA. 

Pharmaceutical companies are all too familiar with transparency requirements. The FDA Amendments Act expands reporting of clinical research programs, research study results, and drug safety information. Disclosure of company payments to researchers and doctors is on the rise, along with public posting of drug costs and coverage.  

A prominent component of the transparency movement is to broaden disclosure of financial interests of investigators involved in clinical research on new drugs and medical products. The aim is to prevent researchers from fudging the data or skewing results in order to bring new treatments to market—and benefit the investigator financially in the process. 

To this end, FDA and the National Institutes of Health (NIH) require investigators to report significant payments from sponsors, proprietary interests in a test product, and equity in a sponsor's company. But reformers are pressing to expand disclosure of manufacturer payments to researchers in order to minimize the role of money in shaping new drug development and utilization. 

The Health and Human Services' Office of the Inspectors General (OIG) issued a report in January 2009

  recommending that sponsors of clinical trials disclose investigator financial information to FDA before studies begin, instead of when the company files a new drug application (NDA), as now required by FDA. The change would allow FDA inspectors to review financial reports when they inspect clinical sites and would increase reporting rates by clinicians, which the OIG says is way too low. 

FDA currently advises sponsors to collect financial information whenever they engage an investigator during the research process to be sure there will be no serious conflicts-of-interest that could compromise study outcomes. But the OIG found that little financial data was listed in some 100 NDAs filed in 2007, and many of the applications contained no investigator reports. 

Sponsors object that earlier filing would bring in reports on many investigators involved in studies that turn out to provide little support for product efficacy. And FDA fears being inundated by financial records that turn out to be unimportant. 

NIH also has been under fire from Congress for failing to adequately police financial conflicts-of-interest among academic researchers receiving federal grants. NIH requires grantees to report payments from drug companies that exceed $10,000, but investigators with Sen. Charles Grassley (R-IA), ranking Republican on the Senate Finance Committee, have uncovered prominent academics who fail to report millions in payments. This includes a number of psychiatrists involved in testing and presenting on widely used antidepressants. 

NIH officials agree more needs to be done to police such activity, but they don't want to start examining the tax returns of thousands of researchers. 

Transparency requirements also are expanding pharma disclosure of payments and gifts to all health professionals. States are passing laws that require manufacturers to disclose payments and gifts to health care professionals, as seen in Minnesota, Vermont, West Virginia, Maine, and most recently in Massachusetts. 

A long list of states is considering similar statutes, including California, Texas, Illinois, and New York. These laws generally seek data on fees, gifts, and educational grants to health providers and organizations, but policies vary as to which expenditures have to be disclosed and when. 

Manufacturers also have to report a range of pricing information to state governments eager to ensure that their Medicaid programs get best prices. California, Maine, New Mexico, Texas, and Vermont have adopted laws that require companies to submit information on drugs sold in the state to facilitate comparison of average manufacturer prices (AMPs) and to Medicaid rates. And Medicare is posting information on drug prices and rebates on its Web site to help beneficiaries understand differences in plan coverage and out-of-pocket costs. 

In addition, federal and state enforcement officials are including disclosure requirements in corporate integrity agreements (CIAs) with drug and medical product companies to resolve allegations of fraudulent promotional and pricing practices. 

Prosecutors have put an "emphasis on transparency" in industry relationships with physicians and results from clinical trials, said U.S. attorney Michael Loucks at CBI's Pharmaceutical Compliance Congress in January. Under a comprehensive CIA negotiated as part of Eli Lilly's record $1.4 billion settlement involving schizophrenia drug Zyprexa, Lilly will post on its Web site quarterly reports on payments to physicians, including speaker and consulting fees, grants, gifts, food, and travel. 

Last year, Cephalon agreed to report all payments to physicians as part of its $375 million settlement with federal and state prosecutors resolving allegations of improper sales and marketing practices involving three therapies. 

In anticipation of more diverse tracking and disclosure requirements, sponsors are establishing their own transparency programs. Pfizer recently joined Eli Lilly, Merck, and GlaxoSmithKline in announcing plans to post data on financial relationships with health professionals, and some companies are setting total annual caps on payments to individual physicians to reduce any appearance of excessive influence. 

Academic research centers similarly are promoting transparency in researcher–industry relationships. 

Harvard Medical School is reviewing its limits on staff stock holdings and income from drug and medical product companies. The Cleveland Clinic announced in December that it would publicly report business relationships of its 1800 staff doctors and scientists with pharmaceutical and medical device makers. Stanford University, the University of Pennsylvania, and branches of the University of California in Los Angeles and San Francisco have adopted stricter conflict-of-interest policies. 

Some medical societies are moving in the same direction. The North American Spine Society announced in January that the 5000 spine surgeons in the organization will disclose all financial ties with medical product companies. 

Diverse federal and state disclosure requirements also are building industry support for federal transparency legislation that would preempt state laws. 

In January, Grassley and Sen. Herb Kohl (D-WI) introduced an updated version of the Physician Payments Sunshine Act, which establishes a federal system for disclosing financial relationships between physicians and manufacturers of drugs and medical products that are covered by Medicare, Medicaid or other government health programs. Companies would have to file reports on payments to physicians over $100 a year (down from a previous $500 threshold) plus any substantial investment interests held by doctors. 

All this information would go into a national database of physician–industry relationships that would allow public and private payers to uncover and assess relationships between industry payments and physician practice patterns. 

The trade-off for manufacturers is supposed to be federal preemption of state disclosure laws that require differing information on payments to physicians. However, it's not clear how comprehensive that preemption will be in any final legislation. 

Meanwhile, companies are establishing data systems able to track a company's "aggregate spend" on research and marketing activities across corporate divisions and product lines. The aim is to collect in one place all company payments to a physician, which may involve clinical research, consulting, and medical education for research programs and products. 

Physicians, though, are not enthusiastic about public access to their prescribing records and practice patterns and recently won a court decision that disclosure of  physician-level Medicare claims data violated the doctors' right to privacy. Employers and insurers sided with the Consumers' Checkbook in arguing that transparency in health care quality and cost information can help identify high quality and efficient care. 

Such legal conflicts reflect the difficulties in establishing disclosure and reporting requirements across the nation's health care system. Physicians may have realistic fears about misinterpretation of practice data. But health reformers regard transparency in health care costs, research practices, and medical product performance as critical to driving down health care expenditures and expanding access to affordable care. 

Jill Wechsler is the Washington editor of 

1. Health and Human Services, Office of the Inspectors General, 

http://oig.hhs.gov/oei/reports/oei-05-07-00730.pdf

View from Washington

Reformers seek disclosure of investigator payments and conflicts of interest.

Transparency Shapes Pharmaceutical R&D

Like any industry, the world of life sciences is in a constant battle for more efficient processes. Of course, with clinical trials there is the additional hassle of having to share extensive amounts of data among the multiple players involved in a trial. 

That's why it is surprising to find that still some 50% of these industry professionals use email as their predominant method of sharing high-value information, according to an Intralink's poll (New York, NY). 

 Communication Methods in Clinical Trials 

Even more surprising, the survey showed that following email as the top means for transferring information among clinical trials professionals was fax and overnight courier. 

When weeks can potentially equal millions in a study, it seems that overnight mail and fax would certainly be the least likely candidates. But still, almost 15% are using fax and almost 14% are using overnight mail. 

Though there is an obvious level of comfort in using these traditional methods of communication, "they come up short because they lack the security and audit capabilities you're looking for in this kind of process," noted Alison Shurell, vice president of life sciences product marketing for Intralinks. 

The obvious risk in using such methods when sharing sensitive documents, Shurell told 

, is that "emails can get intercepted and sent to the wrong address, faxes are often left on the machine, and other people can see that. The other thing is that with email and fax it is very difficult to establish an audit trail—how do you know that who you sent it to got it, how do you know they picked it up?" 

Fortunately, for those ready to adopt a new information exchange approach, there are other options of communication methods specifically designed for these types of processes. Web-based communication tools, such as Intralinks' Online Workspace, offer a service that requires "no installation of software on anyone's computer. As far as a site or the sponsor, all they need is Web access. They simply go to the Web site, use their unique ID and password to log on, and begin their work," Shurell explained. 

While this type of service may rise above email, fax, and overnight mail on the issues of time, security, and money, it of course has the potential of facing the common resistance that typically emerges when implementing a new system over an already established one. 

Quintiles' Site Start Up Director Lee Farrell explained that when implementing Intralinks' Web-based solution, getting clinical sites and their own employees to adopt the system was one of their biggest challenges. 

And with 61% of respondents declaring the greatest challenge when beginning a new study is getting research sites on-board quickly, requesting them to adopt a new communication system may make this an even greater challenge. 

Farrell also sited training and changes in the established process for collecting clinical site, regulatory, and investigator contracts as challenges that her company had faced. 

When asked what would be most important if the decision was made to implement a technology solution, the poll showed that 40% of respondents were concerned with security, 23% with ease and flexibility of use, and 17% with speed of information sharing. 

 So, though getting clinical sites to climb on board with the additional requirement of adopting a Web-based technology may be an inevitable hurdle, overcoming the issues of time and security may be worth the leap.

News

Uncovering the risky communication methods of clinical trials professionals, while discovering a potential Web-based replacement.

Poll Finds Ironic Inefficiency

To be sure, the road to clinical trials transparency is paved with good intentions—from the architects of 

, to the sponsors, to the "external" stakeholders. But this road is proving to be a difficult one to travel. 

 and contractor to the National Library of Medicine, offered some insights into these difficulties at a Center for Business Intelligence (CBI) conference last month in London. The Clinical Trials Registries and Results Databases conference—the first held outside the United States—covered global and U.S. requirements. 

Basic results reporting requirements went into effect September 27, 2008. As of last month, 250-plus results were submitted. Of those, approximately 46 had been "published" or made available on the site. So where are the balance of the results? Back to the sponsors for data clarification and cleanup. 

"The data we have been getting is difficult to understand and the quality is pretty bad," Ide told the audience via teleconference. He provided actual examples of data errors, which are housed on the 

However, one attendee responsible for transparency compliance at a large global pharma told 

 that the company had submitted 40 results to the 

 PRS database, and none have been approved. 

Ide seemed optimistic that most of these issues were just a part of the learning curve. He recommended that sponsors input one study at a time. "Go through one, and learn lessons from that," he said. Also, people intimately involved with the study, along with a statistician, were recommended by Ide for the results input responsibility. 

Ide also said that his group has its own learning curve. "We are considering adding rules into the database so information is flagged up front (for example on data inconsistencies) on the input and then it can be more streamlined." 

To wit, many of the attendees who were appointed or adopted to take on these requirements spanned regulatory to legal (see sidebar). Further, the functions related to the registries and results include protocol writing, study report preparation, Form FDA 3674 certification, just to name a few. 

The challenges with these many functions and stakeholders according to Paarlberg are keeping SOPs up to date and the training that goes along with that. Many attendees questioned the ability—or rather inability—of data to be kept standardized with the different systems. 

Many countries—such as Israel, Italy, and Taiwan—have a registries mandate in place, said presenter John McKenney, SEC Associates. The Czech Republic posts the trials itself, and other countries are discussing the implementation and responsibility aspects of trial registration. Following all of the countries' requirements is also a challenge for sponsors. 

 and the United States for guidance in this area. The U.S. leads in the results posting, and most sponsors must conform to market their drugs here. 

 is scheduled for April 20. Coincidentally, CBI's 4th Forum on Clinical Trials Registries and Results Databases will be held in Arlington, VA, April 21–22. Nicholas Ide is set to offer an update from this Spring Meeting at the CBI event.—

Global News

London conference underscores foggy climate surrounding clinicaltrials.gov

Closer to Transparency

Since this past summer, the most common questions that I receive during my conference and meeting presentations revolve around the current recession and its impact on clinical research. 

Though reluctant to openly admit it, inquisitors are responding to growing concerns about announced layoffs, tight financial markets that once fed smaller company R&D spending, and project postponements and cancellations. 

The questions are not easily answered. Historically, I explain, clinical research has weathered recessionary periods extremely well, leading analysts and insiders to conclude that biopharmaceutical R&D is somewhat immune to economic cycles. 

A Tufts CSDD analysis of the past five recessions since 1973 shows that R&D spending continues to grow, though at a more modest rate compared with healthy economic periods. Active Phase I–III project volume continued to rise steadily during the past five recessions. And, according to PhRMA, clinical research personnel growth has typically been flat or has slightly increased during recessionary periods. 

I add, however, that the current economic crisis appears to be an anomaly. 

The impact of this global recession has hit clinical research squarely and broadly, although a few select sponsors and CROs have emerged unscathed and eager to pursue market opportunities. 

Pharmaceutical and large biotechnology companies have announced that they will be terminating—or leaving unfilled—more than 50,000 positions, of which about 10% will come from R&D. Additionally, a number of major drug development sponsors have announced plans to focus research priorities. 

In the past few months alone, for example, GlaxoSmithKline has announced its plans to eliminate hundreds of research positions as part of an operations overhaul. AstraZeneca and Merck also announced plans to cut thousands of positions worldwide—including those within R&D—during the next several years. Pfizer, which recently acquired Wyeth, reports that it plans to eliminate 19,500 jobs—or 15% of its combined workforce. 

In addition, Pfizer indicated that cardiovascular disease, long a major focus of its innovation, is not a core R&D area of interest at this time. 

After cutting 1200 jobs a year ago, Abbott Labs announced that it will be eliminating another 1000 jobs. Belgium's UCB Pharma reported that it would cut 2000 jobs, or 17% of its workforce. And Procter & Gamble is now apparently looking to pull out of the drugmaking business altogether. 

Amidst downsizings and consolidation, there is a smattering of positive news. 

Sponsors with very strong pipelines have reported solid sales and profit growth during the current recession. As such, rumors are circulating that some of these top-performing companies are attractive takeover candidates. 

Bristol-Myers Squibb, for example, posted very strong revenue and earnings growth in 2008. Schering-Plough and Novartis also posted very strong financial performance in 2008. Novo Nordisk reported a 138% increase in net income for fourth quarter 2008. 

For small pharmaceutical and biotechnology companies, the current operating environment is particularly volatile. Many of these companies face the bleak prospect of scarce funding from capital markets and major biopharmaceutical companies. 

There are numerous cases, at this time, of financially distressed small biopharmaceutical companies roiled by the current operating climate. 

To name a few: Myocor Inc., which had a promising atrial defibrillation device, folded this past October. Orchestra Therapeutics, while developing a treatment for multiple sclerosis, filed for Chapter 7 bankruptcy the same month. Titan, a small biopharmaceutical company focused primarily on CNS disorders, significantly downsized this past December. Altus Pharmaceuticals announced it is cutting 75% of its workforce—or 107 jobs—and will reduce its research focus to a single program. 

Economic uncertainty is driving much higher levels of cautious program management among private sector clinical research sponsors. 

Based on anecdotal reports, sponsors are taking a far more conservative approach to new study starts. They are suspending and terminating large numbers of programs. And they're placing more emphasis on early and substantial justification to continue funding development programs. 

Service providers (e.g., CROs, investigative sites, and patient recruitment companies) note that industry sponsors have been eliminating programs and focusing on priority projects with tight performance timelines and costs. 

Sponsors are also becoming more selective about what, as well as to whom, they outsource to better capitalize on in-house competencies. 

A number of CROs reported very strong 2008 performance due to rising sponsor reliance on outsourcing to handle capacity needs. Recently, PharmaNet stated that a high number of postponed and canceled contracts have forced it to adjust its financial forecasts for 2009. 

In its December 31, 2008, financial statement, Parexel noted that a small biopharmaceutical company client was filing for bankruptcy protection and would no longer fund its late-stage clinical research program. 

An independent institutional review board (IRB) recently told me that on a single day in early February it had four major studies terminated or reduced in size for reasons unrelated to the product's safety profile. 

Investigative sites are reporting widespread postponements and cancellations of planned work. In response, sites have been aggressively pursuing whatever clinical trial opportunities they can find with sponsors and CROs to replace lost study volume. 

Sites overall report that they're in good shape if they are able to execute work already on their books, but the pipeline seems uncommonly light for the second and third quarters of 2009. 

Many clinical trials postponed in the fourth quarter of 2008 have yet to be initiated. Investigative sites report that sponsors aren't even engaged in pretrial work with the sites selected to conduct them. Several sites recently told me that they were forced to write off significantly higher levels of bad debt or uncollectible receivables on their books due to this recession. 

The recent volume of merger and acquisition activity in the biopharmaceutical industry has been high, and it is expected to accelerate in 2009 and 2010, as the climate transitions to that of a buyer's market. 

Notable transactions during 2008 include Takeda Pharmaceutical's acquisition of Millenium Pharmaceuticals, Teva Pharmaceuticals acquisition of Barr Pharmaceuticals, and King Pharmaceuticals $1.6 billion purchase of Alpharma. In early 2009, Pfizer acquired Wyeth, Roche made a hostile bid for Genentech, and Astellas made a $1 billion unsolicited bid for CV Therapeutics. 

Tufts CSDD analysis of M&A transactions shows that combined entities typically limit or reduce R&D spending to accommodate integration challenges and instability. The rising volume of mergers and acquisitions in the current operating environment highlights another unusual condition of this recession. The period of caution and constraint might be extended beyond historical durations. 

For now, clinical research professionals remain guardedly optimistic for 2009. A recent survey of the CEOs of PhRMA-member companies finds that one-third is confident they will continue to see revenue and earnings growth this year. The remaining two-thirds project an economic recovery in 2010. 

In my informal surveys taken at conferences and presentations, sponsors, CROs, and investigative sites largely anticipate that the clinical research industry will emerge healthier once the global economy has recovered. 

Specifically, professionals note that financially distressed markets weed out unhealthy players and free up qualified talent, offering a variety of organizations new or expanded expertise. 

The current environment forces all players to restructure and manage their operations more leanly through lowering both variable and fixed operating costs. Dependence on outsourcing will continue to grow and may finally, out of necessity, spur more effective collaboration models. 

The uncertainties of a volatile recession speak to the need to improve the quality and frequency of communication between sponsors, CROs, and sites in order to manage project suspensions and terminations responsibly and ethically. And sponsors and CROs must be mindful of site cash flow needs in order to preserve and support their most valued investigative sites. 

As I've noted in earlier columns, most sites are operating with very tight margins and poor cash flow—it takes the typical site more than 130 days on average to get paid for work performed. 

Most professionals leave me with the impression that no small measure of hope and optimism will be required to ride out this storm. 

				"Although the current recession may be different," observed one colleague recently, "the name of the game is still about hunkering down, focusing on performance, and making infrastructure and process improvements." 			

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

Clinical Trial Insights

Drug development, largely immune to past economic downturns, now faces a different climate.

Is Clinical Research Recession Proof?

In the days when paper ruled, the filing cabinet was its castle. Then, with the transition from paper to computers came the advent of electronic content management (ECM). And voila: Data suddenly had a new home. 

 Virtify's Executive VP, Commercial Operations, Stephen Bergson (left) and President Satish Tadikonda, PhD. 

In the life sciences, Hopkinton, MA-based EMC dominates the "housing" market. And after more than a decade on the scene, the company's ECM platform Documentum will maintain its first place spot moving forward, says Craig Le Clair, an analyst for Forrester Research in Cambridge, MA. 

It's the maturity of EMC's product and the fact that the company targeted the pharma market when it built Documentum that most credit for its stronghold. But in recent years, a mix-and-match approach to electronically managing content has emerged. 

 "One of the most powerful combinations in the market is to take [Microsoft's] SharePoint at the top and link it to Documentum," says Jeff Klein, head of global product, marketing, sales and development for CSC (Falls Church, VA), which develops content management solution applications for both Documentum (FirstDoc) and SharePoint (FirstPoint). 

It's a front-end, back-end combination that, as Klein explained, allows users to keep Documentum as their ECM platform at the bottom while using SharePoint up top at the user interface level. This tiering structure harnesses the strengths of both products: Documentum's enterprise-class content management system and SharePoint's intuitive and familiar interface and collaborative architecture. 

According to EMC's Grego Kosinski, director of product marketing, content management and archiving division, strong integration was the result of dual customers who asked for it. 

 "From the beginning, the two companies worked together to ensure that the EMC Documentum enterprise content management platform was fully tested, certified on, integrated with, and supported the Microsoft environment—SQL server, Office, and Windows," said Kosinski, "our joint customers demanded this level of integration." 

Today, of course, SharePoint is also part of the supported environment. But as Michael Naimoli, director of U.S. Life Sciences at Microsoft, points out, these two companies may be corporate partners across verticals, but it's still a coopetition.  

"Our products can work beautifully with Documentum," Naimoli explained, "but our message to our life science customers is, 'you can work with the content at the server level as well,'" referring to MOSS, the company's own document management system. 

Speaking of messages, Virtify's (Cambridge, MA) is as dynamic as its solutions: "We are taking the game to a different level," says the company's President Satish Tadikonda, PhD. Think: dynamic content management. 

That's how Tadikonda, whose company has been around for six years, describes "it"—that is, Virtify's XML-based platform, Virtx. 

Introduced in 2008, Virtx is unlike traditional ECM systems in that it's not document centric but document independent and content focused. As Tadikonda explained, "We are separating a document away from the content." So, a document such as a protocol is made up of different "intelligent" (i.e., self-identifying) components—let's say Sections 1, 2, 3—and the user can create content for each one separately. 

This type of set-up, where the document is essentially broken down into pieces, or fragments, allows multiple people to work on the same document online in real time. 

With the same ease, users can update content. For example, if a line needs to be deleted from Section 3 in document Z, by deleting that line from the "parent" document, every document that contains Section 3 will automatically be updated. 

"That means you are repurposing and reusing the same content across documents," explained Tadikonda. It's a create once, repurpose many times approach, which is accomplished in a Microsoft Word-like environment. 

On the scene with electronic content management.

Applied Clinical Trials-03-01-2009

Putting a Face on EDC

Patient Power

Transparency Shapes Pharmaceutical R&D

Poll Finds Ironic Inefficiency

Closer to Transparency

Is Clinical Research Recession Proof?

Managing Content in 2009

Eliminate the Disconnect in a Systems Approach

What I Learned as a Subject

Risk Response: Constructing a Plan

EU-Born HIV Study: History in the Making

eClinical Software: March 2009

Business and People Update March 2009