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Feature Article

Eli Hauser and Paul Bleicher No matter how much a company spends on risk management, it can never prevent all loss. But setting priorities and establishing a risk management strategy can minimize the potential consequences.

Data Delivery During Crisis

Spring is just around the corner, and with its arrival comes an annual ritual for my householdspring cleaning. Although I am not generally a big fan of this activity, there is one aspect that I do enjoy. Every year I open up another few boxes from the last centuryboxes from college, medical school, and other bygone days. Each one is a little time capsule of memories. Old newspapers, photographs, and other memorabilia recall events that are long since past. Each year I find that some of my memories are difficult to enjoy, because the medium on which the information was recorded is no longer readable. Unfortunately, the same issues that led to the loss of my memories can spell disaster for companies that are vitally dependent on their digital data.

It is worth taking a look at a few items that I pulled out of one of my boxes last year, and consider the reasons that they are unreadable. Lots of things in the box are a bit faded, but otherwise as good as new. Black and white photographs from the early 1900s dont look all that much different from when they were new. Color photos from the 1960s may be faded, but the image is clear. The first big problem is an eight-track tape of the Mamas and the Papas. I dont think I am going to be listening to that anytime soon! I dont remember the last time I saw an eight-track tape player outsideor for that matter, insidea museum. Thank goodness somebody preserved the songs in a different format and had them transferred to CDs, where they will last foreveror will they?Next, I found an old computer chess program for my Apple IIe. Unfortunately, I threw out that computer a number of years ago during another annual spring cleaning. Even though the Apple IIe was sold until 1993, it seems hopelessly out-of-date. Perhaps I could just put the 5.25-inch floppy disk in my current computer. Not too many of those around the office, these days. 

Finally, I unearthed a videotape from years ago. Thankfully, it is VHS, not Betamax. I put it into the VCR and voilaa lot of static and very, very poor images. It seems that New England conditions in my attic are not all that friendly to magnetic tapes.

By now, I am sure that most of you see the direct parallels between these stories and the data collected during pharmaceutical development. Drug development is becoming more and more data intensive as our ability to collect and record data increases. In the past, drug discovery often involved the screening of a finite number of compounds against a specific assay or disease model. Today, genomic analysis, modeling, and high throughput screening of combinatorial libraries are generating huge amounts of data. Even clinical trials can now involve continuous monitoring through telemetry with the potential for generation of megabytes of information on a single subject. A small portion of this huge amount of data is extremely valuable today and will be in the future.


These real world examples have clear parallels in the issues of data obsolescence in pharmaceutical data. First, think about those eight-tracks, Betamax tapes, and 5.25-inch floppy disks. Each is an example of a recording medium that has become obsolete. While it is theoretically possible to find someone with a player for one of these formats, you would have to look far and wide. 

 Media obsolescence can make orphans of data in the clinical world as well. Certainly, older reel-to-reel mainframe data tapes, 8-inch floppy disks, paper tapes, and punch card data would be hard to resurrect today in most settings. Extracting data from those formats would be costly and fraught with challenges. Yet, a significant amount of clinical trial data for currently approved drugs exists in just those formats. 

Although these examples are somewhat obvious, more subtle examples abound. Only 10 years ago I backed up all of my academic data onto a tape-based portable hard drive for a Macintosh computer. Today, I dont own a Macintosh and dont know where to find the particular specialized hardware I would need to get access to that data.

Obsolescence also applies to the software and hardware necessary to read data files. Since I tossed my Apple IIe, I cannot run my chess program. More painful, however, is the loss of access to five years worth of word processing files that I produced with the DOS-based Leading Edge Word Processor. Back in the early days of PCs, there were dozens of choices in word processors. In 1987, I bought an inexpensive Leading Edge PC that came with its own word processor. We all know what has happened with word processorsfirst Word Perfect seemed to command a lead in our industry, but now Microsoft Word has a dominant position in the market. MS Word can read some older files from other software, such as Word Perfect 5.0 or 6.0, but to read earlier versions of Word Perfect requires a special translation program that might be difficult to obtain. The results would be only fair, because much of the formatting is lost in translation. 

It would probably be difficult or expensive to find translation software that would read original Leading Edge Word Processor files. As I remember, this word processor had its own proprietary file format so that the words themselves arent even retrievable from those files. Software obsolescence virtually destroyed my data.

 Software and hardware obsolescence are special challenges in imaging, especially diagnostic imaging. In the early days of any technology, there are rarely any standards for recording data. With diagnostic imaging, this is a very significant issue. In order to be able to read and analyze data, it is essential to have hardware and software that can manage these images. Not too long ago I had a tour of a contract research organization that specializes in managing diagnostic images. They own just about every type of proprietary file reader that exists for those imagesin at least one case they have the last known working copy of these machines. The hardware companies that produced the data readers may be out of business, and the specifications for the readers may no longer exist. Once there is no longer a reader, there is no longer data. 


Data can be lost even if it is written in a current format. Many of us assume that digital media are permanent. This is especially the case with CDs, which appear permanent and indestructible. Yet, those static-ridden analog VHS images are indicative of another issue with medialimitations on the longevity of data. Various digital media are also susceptible to environmental variations in temperature, humidity, oxidation, magnetic and sunlight damage. Most of us have had the shocking experience of putting an important floppy disk into a computer and getting the message: The floppy disk in the A: drive is not formatted. Would you like to format it now? That doesnt mean that all the data have been wiped clean. If the data are text- or ASCII-based, a forensic computer scientist could recover most, if not all, of it. But environmental influences may have corrupted some of the data. If the damage was done to a program or to encrypted data, there is very little that can be done to recover the data. 

To avoid this issue, most of us back up our data. If we store our backups in another location, under environmental control, we assume that we are safewhich is not necessarily true. For example, many individual computer users back up their data to Zip or Jaz drives. A reliable source has documented a very serious data-destroying fault with some early drives of this type, called the Click of Death. (If you use these drives, see: http://grc.com/codfaq1.htm). Unfortunately, I have been a victim of this particular phenomenon. Corporate IT (information technology) departments typically do backups to digital tapes. It is not uncommon for some backup tapes or portions of backup tapes to fail when they are most neededwhen data has been lost. 

Most recently, recordable CDs (CD-R) have been extensively used for the backup of data. For the past several years there has been a raging debate in the computer industry about the longevity of CD-Rs. The very expensive Gold CDs supposedly have a usable life of over 100 years. Some argue, however, that low-end conventional CD-Rs may be reliable for only 5 to10 years. Whether or not CD-Rs have a limited shelf life in times relevant to clinical development, it is clear that they can be easily damaged by heat and mishandling. A recent report suggests that CDs stored in humid environments can actually be eaten and destroyed by a Geotrichum fungus (www.nature.com/ nsu/010628/010628-11.html). We may not notice loss of data in damaged music CDsthe players are designed to fill-in for lost databut loss of information in clinical data CDs could be a serious problem.

 One strategy for retaining data quality is to migrate the data from an older format to a newer format. Although this strategy can keep the data fresh, it needs to be done very carefully, with a validated migration path. Without this, there is a significant risk that data will be lost as part of the transfer, or changed in subtle and possibly undetectable ways. Formatting, metadata, and footnotes to data are often lost or changed in the transfer process. Even worse, the actual data itself may be changed. In a 1998 

 article, the FDA reported that some data that had been migrated from one operating system (OS) to another was randomly off by up to eight digits. Once the migration has occurred, any changes to the data are permanent because the original is usually destroyed.


Clearly, our data is at risk. So, what strategy do we follow? The most important first step is to have a strategy at allmany companies dont think about these issues. Develop a strategy, revisit it often, and make sure that it is implemented routinely. The first consideration should be the file format for data storage. All other things being equal, it is best to chose file formats, media writers and readers, and hardware that are widely adopted and appear to be heading toward being a data standard. If that is not possible, try to go with the leading front of the mainstream. Dont chose an older, nonstandard technologythe file format may be on the road to obscurity. Similarly, dont choose a hot, cutting-edge technology from a company that may not exist a year later. If possible, keep to a minimum the number of different formats in which data is stored. 

Future retrieval of vital clinical data depends on having a strategy to deal with the rapid obsolescence of computer software and hardware.

Diamonds May Be Forever, But Data?

The other day I was talking with a colleague of mine across the pond about the current state of technology in clinical research. We started talking about terminologyabout the meanings and pronunciation of words, the way some people pronounce a certain nut 

Pronunciation makes little difference when talking about pecan pie. But in the world of clinical research, with its continual flow of new technologies with unique sets of terms and definitions, differences in pronunciation and meanings can cause problems in our clinical projects. Such problems are rarely as amusing as that created in a room full of cardiologists when an Austrian colleague, who had trouble saying 

 correctly, used the term feel it up. Or theres my friend in France for whom the phrase we have to focus never comes out quite sounding like he meant it to.

Effective communication is one of the three Cs that are key enablers for all relationships (the other two are collaboration and culture). When working with other people its important to know that communication styles differ from culture to culture; the way things are phrased and the timing of conversations are different. In Italy, for example, you use first names only with good friends, and in Japan you never use first names. In the Netherlands you may talk about international affairs but not religion, and in Poland decision making is slow and deliberate. In Texas, it is 

. When you understand issues of that sort, youve got it wired! 

Recently, I saw a name listed incorrectly next to a Site ID on one of our forms. I repeated several times, No, the name should be Juan to the database administrator (DBA) in charge of entering the names of clinical research associates and their corresponding sites into our electronic data capture system. He finally wrote the number 1 after the Site ID to prevent me from repeating myself a sixth time. Only then did I realize that the DBA was not hearing the name 

. Accents can trigger miscommunication. Our DBA heard me saying 

People bring their own expectations, languages, and cultures to an interaction. Keeping this in mind is crucial as we speak with our clients and colleaguesand as they speak with us about their needs and concerns. We must consider the perspective from which they approach our projects and avoid assuming that we understand.

As I continue to work and learn in this new technology environment, Im sometimes perplexed by all the terms people throw around. To some developers, ASP stands for application service provider; to others it means active server page. And dont confuse ASP with ISP (internet service provider). As long as I mentioned developers, Ill lend this other tidbit of advice: They dont call themselves 

 anymore. As when speaking a foreign language, what you hear and what you conceptualize can be two completely different things. 

I spent many years traveling back and forth between Austin, Texas, and Europe on business. One of the areas that I tried to improve was speaking other languages so that I could communicate better. In France, I once thought I told the person at the hotel, This is my luggage. Can you have someone take it to my room? What I actually said was, I am baggage. Take me to my room. The intent was there but the meaning just didnt quite come out right. 

It took months before I stopped thinking cardiopulmonary resuscitation when hearing mention of CPR, which, as it was being used, stands for computer-based patient record. Terms arent always intuitive, so it takes time to catch on and truly understand whats being said. When Im in a room with techies, and I hear talk about downtime, I need to remind myself that theyre not talking about time spent unwinding after a long, hard day in the clinic. With all of these differencespronunciation, enunciation, and meaningI began to wonder if this is one of the reasons why were having difficulty communicating not only here but globally as wellparticularly on new technology projects.

So is it electronic data capture (EDC) or remote data entry (RDE), and, at the end of the day, whats really the difference? Believe me, I spent some time thinking about this (and, yes, I do have a life). In my intellectual pursuit of logical reasoning, I hypothesized that perhaps people consider remote data entry as a function and EDC as the capture of data in an electronic format. Youll be happy to know with all that brainpower spent, when I researched the topic I found that there was no real difference except that EDC is the newer term for the new systems. The terms have been used loosely and interchangeably globally. CDISC (the Clinical Data Interchange Standards Consortium) defines EDC as:

Collecting or acquiring data as a permanent electronic record (e.g. using data collection systems or applications that are modem-based, web-based, optical mark/character recognition, or involve audio text, interactive voice response, graphical interfaces, clinical laboratory interfaces, or touch screens) with or without a human interface. (CDISC Note: permanent in the context of these definitions implies that any changes made to the electronic data are recorded via an audit trail.)

If a distinction is to be made, according to CDISC, it is this: With EDC, data are actually entered at the point of origin (the investigator site), while RDE implies that the data are entered remotelya rather interesting point of view considering that data are actually being entered at the site where the data are gathered.

Effective communication requires more than recognizing differences and memorizing definitions. It requires respect. The terms of the trade (technology in clinical research) are what they are, and how theyre applied relates to you wherever you are on your learning curve. How you write, how you speak, how you present yourself, your respect for differences, your ability to be flexible, your willingness to see the other point of view, and time and patience will prove fruitful. 

With all our differences, we have many similarities. We all want to see our patients improve. We all want our projects to run smoothly. We want to be able to spend more time doing the things that matter to us. We want to have technology available that makes sense. And, we dont mind if its called EDC or RDE. Whats crucial is ensuring that as you roll out an EDC project, you and your vendor are always on the same page. Those who have read my previous Notes from the Field know that my mantra is Always stop and ask questions if youre unsure.

 Ask for an explanation of any unfamiliar terms. Dont pretend that you understand. By talking and working toward understanding we can have a global community that bridges the worlds of technology and research.

Use your technology vendors as tutors, of sorts. Learn from them about what you need to focus on. I know, were used to looking up and studying what we dont understand. But when the topic is technology, its also important to communicate with your vendor. Its also much easier than trying to sift through all of the books out there on this topic.

Back to my friend across the pond: We still continue to discuss the varying terminology, even for simple items. What I refer to as a 

. As a friend from Germany explained to me, The phone is handy, you get to talk with anyone at any time, and you never have to go anywhere. Besides, you hold it with your hand. Now, thats intuitive.


1. Donna Hellsten, What to Ask EDC Vendors, 

2. Donna Hellsten, Planning an EDC Clinical Trial, 

is vice president of Global Client Services, CB Technologies, Inc., 350 Eagleview Blvd., Exton, PA 19341, (610) 280-7400, fax (610) 280-0440, email: d_hellsten@cbtech.com. She would love to hear your miscommunication stories and encourages readers to send her funny, interesting or poignant stories from the field.

PhD, is client services manager for CB Technologies.

*To whom correspondence should be addressed.

Notes from the Field

EDC, RDE, OCR: We speak the same language–or do we?

To enhance its ability to protect the safety of clinical trial subjectsand to ensure the accuracy of data developed to support  New Drug ApplicationsFDA set out to clarify its policy on the use of Data Monitoring Committees. Also known as Data and Safety Monitoring Boards, DMCs oversee safety issues and track treatment effects during the course of a clinical study. 

FDAs draft Guidance for Clinical Trial Sponsors on the Establishment and Operation of Clinical Trial Data Monitoring Committees (issued November 2001) describes the roles, responsibilities, and operations of DMCs. The agency is seeking public comment on how the policy might be revised and implemented. To this end, it held a public meeting 27 November 2001 to hear from affected parties. The guidance applies to clinical studies of drugs, biologics, and medical devices, whether sponsored by industry or government. FDA hopes to finalize the policy by the end of this year. 

Many members of the research community consider the FDA draft document overly prescriptive, particularly for investigators at academic research centers, which increasingly participate in clinical trials for FDA-regulated products. Although agency officials insist that a guidance is nonbinding and merely reflects the agencys current thinking, researchers and sponsors maintain that the proposal will become the gold standard for both commercial and academic research. With FDA and the Department of Health and Human Services (HHS) Office for Human Research Protections (OHRP) shutting down research organizations that fail to comply with the rules, few study sponsors are likely to ignore agency guidance in this area. OHRP director Greg Koski commented at the November meeting that FDAs draft guidance is not a fait accompli but aims to stimulate discussion. He sees this effort to define the way DMCs are constituted and interact with institutional review boards (IRBs) as part of the larger task of remodeling the federal system for monitoring clinical research. Developing guidance on DMCs, he says, should impose a greater level of uniformity on government and commercial clinical research. 


Study sponsors have used DMCs for years, primarily to oversee large, randomized multicenter clinical studies supported by grants from the National Institutes of Health (NIH) or sponsored by the Veterans Administration. The aim is to have an independent panel of experts review accumulating data on study safety, efficacy, and conduct, particularly for trials with mortality or major morbidity endpoints, to provide data for objective interim assessments. The DMC advises the sponsor on the continuing safety of trial participants and the validity and scientific merit of the study. 

FDA regulations require DMC use only for clinical trials involving emergency research where informed consent is not feasible. Such studies usually involve life-threatening situations, and oversight by an independent data monitoring committee aims to provide added protections to subjects. References to DMC operations also appear in several guidance documents on clinical trial conduct developed through the International Conference on Harmonisation (ICH). The ICH Guideline for Good Clinical Practice suggests the use of such independent panels to assess the progress of a clinical trial and its safety data in order to recommend whether the sponsor should continue, modify, or stop a trial. Other ICH policies describe DMC composition and operating procedures.

In the last few years, sponsors of commercial trials have used DMCs more often, particularly for studies with major endpoints, explained Susan Ellenberg (director, Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research), who chairs the FDA working group developing the agencys DMC guidance. An increase in industry and government research collaboration, plus heightened public concern about bias and conflicts of interest in clinical trials, have stimulated DMC oversight.

The trend accelerated noticeably following publication of a 1998 report on institutional review board operations from the Office of the Inspector General (OIG) of the HHS. The OIG recommended that DMCs be used more frequently to oversee certain clinical trials and to review adverse events occurring during a trials progress. To encourage this, the OIG called for HHS to more clearly specify DMC requirements and operations. 

In response, FDA formed a committee with representatives from CBER, CDER (Center for Drug Evaluation and Research), CDRH (Center for Devices and Radiological Health), and the Office of Compliance (OC), which conducts field inspections of clinical sites to support applications filed with FDA. The panel published the draft guidance on 19 November 2001. It describes models for DMC operations and functions. 


A major concern for sponsors is that FDA and NIH are moving toward recommending DMCs for a broader range of clinical investigations. Although the government requires that sponsors monitor safety issues and report adverse events related to all trials, until now no DMC has been needed in most cases. FDAs draft guidance encourages increased use of DMCs for Phase 1 and Phase 2 studies that raise issues about risk and objectivity. Ellenberg said at the November meeting that a DMC might be useful if an early trial presents important safety concerns, but that this would be a rare occurrence for most Phase 1 trials. 

The key issue is where FDA and HHS officials will draw the line. Today, all NIH-funded interventional studies undergo review by a DMC as well as an IRB. While the guidance does not aim to lay out any single model for DMC operation, it outlines three key factors that should determine when a sponsor decides to form an outside review panel: risk, practicality, and scientific validity.

 Key factors include use of mortality or major morbidity as primary or secondary endpoints, whether the study involves a highly novel treatment that lacks prior information on clinical safety, enrollment of a highly vulnerable study population (children, elderly subjects, seriously ill patients, for example), and likelihood of adverse events. The guidance states that trials that are large, of long duration and multicenter raise more possibility of safety issues because of the greater overall exposure and the likelihood of unanticipated adverse events. 

A DMC also may help deal with ethical issues that may arise if a product performs very well and the sponsor needs objective advice on discontinuing a control arm. A favorable or unfavorable early result might ethically require study termination before planned completion.

 On the practical side, a sponsor has to consider whether a trial is sufficiently large and long-term to allow time for a DMC to analyze safety issues. Added concerns are whether the sponsor can afford to underwrite a DMC program and whether enough experts are available to serve on a panel.

Need for DMC to ensure scientific validity.

 A DMC is particularly useful when there are serious concerns about bias and lack of independence by sponsor or investigators. Changing information or circumstances may require the sponsor to modify the protocol during a trial. 


The issue of access to unblinded interim study datawho should have access and whenhas emerged as a prime point of debate about the proposed policy. Study sponsors need to be able to revise a trial protocol as it proceeds and as new information and situations arise. But to modify a clinical trial protocol without introducing bias and while avoiding premature disclosure of study results, the sponsor should have access only to blinded data, points out Jay Siegel (director, Office of Therapeutics Research and Review, CBER). 

Thus, an important role for a DMC is to provide objective advice on the need to modify or halt a trial based on interim safety and efficacy data. The DMC also can assess adverse events that may be part of the disease process or common in the study population and therefore not likely to appear related to the clinical trial. Such analysis may prompt the DMC to recommend reducing a dose to avoid toxicity or changing a consent form to warn of an emerging safety concern. 

Through this process, the DMC reduces the need for a sponsor to access interim comparative data, which may oblige the company to disseminate that information to study participants and investigators and compromise its ability to manage the trial appropriately. If individuals recommending changes in inclusion criteria, endpoints, or trial size have knowledge of accumulating data, such changes would inevitably impair the credibility of study results, the guidance states. 

A related issue is whether the sponsors own statistician should analyze interim unblinded data. This may raise concerns about how separate the employee is from decision-makers. To avoid conflicts of interest, some experts call for increased use of independent statisticians to review interim data.

The decision by a sponsor to access interim data is a major step and should be discussed with FDA in advance, advises CDER director for medical policy Robert Temple. Early access is necessary if a DMC recommends terminating a study, and FDA should be informed of such a situation. And if early termination arises from data indicating strong benefits from treatment, then FDA wants to know if safety data is adequate, if the benefit has long duration, if subgroups have been assessed sufficiently, and if secondary endpoints are considered, Temple explains.

In addition to using DMCs to monitor a single large trial, sponsors might establish another type of DMC to review an entire developing database, Temple suggests. He describes a DMC Type II to review safety concerns and study design issues arising from a series of smaller, possibly short-term, trials that evaluate relief of symptoms as opposed to treating serious conditions. It may be useful for an outside group to monitor the developing safety database from such studies to make recommendations for future study design. This approach may be especially helpful in dealing with high-risk populations where pooled data may reveal special issues. This broader DMC could sift early study data to be sure that Phase 3 trials cover the desired range of severities and appropriate doses, combinations, and study duration. Moreover, when the investigator has a financial interest in the product or when there are ethical issues involving a study, a DMC may enhance the credibility of research efforts.

SIDEBAR: Data Monitoring Committee Guidance


Once a sponsor decides to use a DMC, the FDA draft guidance provides specifics on how such a panel should operate. An important objective is to clarify the relationship of the sponsor to the DMC, noting that an independent panel will have the sponsor or its representative participate only in open meetings.

 A DMC should have members with expertise in clinical medicine, biostatistics, ethics, pharmacology, epidemiology, and clinical trial methodology, as well as patient or community representatives. Geographic representation, demographics, and other experience may be relevant. Candidates should be assessed to avoid conflicts of interest. The sponsor selects a panel chair based on prior DMC experience and ability to communicate and build consensus. Commitment to the position for the duration of the trial is important.

 These should specify meeting schedule, format for data presentation, data access of members, meeting attendees, assessment of conflicts of interest, and methods and timing for issuing reports. An important point is to clarify what statistical methods and assessments will be used and what thresholds would warrant recommending study termination. 

 Access to coded data, timing and distribution of reports, and importance of strict confidentiality are stressed. 

 Specifies formats for open, closed, and executive sessions and who may attend, and what issues and data will be discussed.            

View from Washington

A proposed policy on Data Monitoring Committee functions and operations raises important issues about the conduct of studies and the evaluation of data.

FDA Promotes DMCs to Enhance Subject Safety

Electronic data capture has a history of mixed results, but evolving technology and major shifts in the drug development market mean the industry should now revisit EDCs benefits. 

During the nearly two decades that electronic data capture has been available, pharmaceutical companies have repeatedly dipped their toes into its waters, then stepped away from serious commitment. But now, with shareholders expecting continued returns of over 20%, research costs increasing faster than sales, and pricing and patents both under pressure, the need to control the cost of clinical research and accelerate time to market is paramount. PricewaterhouseCoopers estimates that the industry will need to reduce the cost of drug development by 20% to over 40%.

Electronic data capture (EDC) has changed significantly and can now be considered an effective way to minimize the cost of clinical research. In fact, PricewaterhouseCoopers estimates that EDC and similar advances can reduce the cost of clinical research by 20%. By understanding those changesand the requirements for implementing the technology successfullypharmaceutical companies can maximize EDCs bottom-line potential. 


Tremendous changes have taken place in the capabilities of electronic data capture technology, in the capacity of EDC vendors, and in corporate experience with EDCchanges that make EDC a reliable tool for significant business advantage. 

 EDC technology has improved dramatically since its introduction in the early 1980s, when DOS-based systems were unable to meet the industrys high standards for validity. Current-generation EDC applications use the Web for data transactions, whether data is being entered online or offline. The advent of UML (Unified Modeling Language), XML (Extensible Markup Language), and portal technology, as well as standards promulgated by the Clinical Data Interchange Standards Consortium (CDISC) are improving the ability to integrate EDC and other key applications. The Internet is an increasingly effective and secure mechanism for data transactions, information sharing, and collaboration, and it is used in other demanding industries such as the securities business. New technologies in the works offer the potential of a true paperless clinical trial. EDC technology is ready to move past the critical early adoption stage and into the early majority stage. 

Vendors have grown in scale, stability, and reliability.

 The large pharmaceutical companies have worried that EDC providers lack the scale and stability to support global clinical development requirements. The business profiles of established EDC vendors are much improved, but vendors have yet to achieve the scale required to meet the needs of a global drug development enterprise performing up to 1000 clinical trials per year. A good vendor assessment processone that focuses on known providers of EDC technologycan yield a successful business relationship. 

Most companies have some experience with EDC

 and plan to increase their use of the technology. An ACRP (Association of Clinical Research Professionals) survey focused specifically on EDC received 229 responses136 from investigator sites, 41 from pharmaceutical or biotech companies, 29 from contract research organizations (CROs), and 59 from other clinical researchrelated sources. The survey indicates that almost half (49%) of the respondents companies had used EDC systems or processes. Of the respondents who had used EDC, close to 80% indicated that their overall experience was either neutral or positive.

 ACRPs annual survey responses indicate that 66% of sites, 60% of CROs, and about 50% of sponsors expect to adopt electronic case report forms (eCRFs) within the next two years

 if it were more broadly applied, evidence suggests. EDC is currently used in only about 10% of clinical trials.

 Those trials are not structured in a way to prove or disprove the efficacy of applying the technology, but other data strongly suggests its potential. 

In one case, EDC reduced the cycle time on case report forms from 45 days to 9 days. Transcription errors were eliminated, and data errors were detected almost immediately, allowing for early intervention. In another case, the database was actually locked on the day of the last subject visit, rather than the more typical three to six months later.

Multiply that by the average 68 trials per New Drug Application (NDA) and the possibilities for reducing time to market are clear. 

By reducing sponsor and investigator time normally spent on transcription errors, out-of-range data values, and similar problems, EDC frees a clinical research associate to focus on source document verification, regulatory compliance, and building relationships with site staff. Earlier data cleanup also allows for quicker and better decisions on whether to continue, expand, or discontinue a study. 


Although pharmaceutical companies may not yet be completely comfortable with current EDC vendors, market forces dictate that drug (and device) development companies make the commitment to achieving maximum feasible value from EDC. Comfort level may increase as larger technology organizations start to consider EDC vendors as acquisition candidates. 

To help pharmaceutical companies go beyond the perpetual piloting syndrome and to get maximum value from EDC implementation, we suggest several essential strategies. 

 Executive support is key to getting the financial commitment and substantial attention to people and process that EDC implementation requires. Only executive support can break down the organizational inertia in the separate silos of typical departmental structure, and the deeply entrenched processes and habits involved in the use of paper systems. Both must be surmounted to realize full worth from EDC.

Implement EDC through a change management process.

 For an EDC solution to succeed, it must be shaped by its key stakeholders. Consensus development will ultimately have more impact on what the company can achieve than will the timetable for deploying hardware. 

Categories to be addressed in assessing the needs of the internal organization are shown with examples in the Change Management box. It is not only critical to involve internal constituencies but also equally important to involve the investigators and their staff members in the planning process in some way. An apparently ideal EDC design will fail if it doesnt take into account the possibility that users may have limited experience with technology.

 must be an important part of the change management process. Standard operating procedures, work processes, and business continuity practices must all be reviewed to see where they need to be modified to support and work with an EDC system.

 is a key part of successful change management. Criteria for determining success must be specified in advance and the metrics used should be appropriate for a short-term assessment. EDC and paper-based systems should be compared on a best test, not stress test basis, making allowances for the learning curve, and for investigator office conditions that may be less than optimal for EDC system implementation. The idea is to compare paper systems with the best possible approximation of the way EDC will perform as a steady state system, not a brand-new one.

Once it is determined whether the pilot program is a success, appropriate next steps may include a direct comparison between EDC and the paper processmeasuring differences and extrapolating the value that the new technology might bring if truly integrated. Or the technology could be rolled out across a number of studies to expand the metrics analysis to include a broader array of variables.

One product of the change management process is a comprehensive implementation plan that addresses all aspects of change needed to maximize the value from an EDC system. This plan will include training requirements, documentation needs, user support requirements, technology administration and security, reporting, cost analysis, decision support, and change controlas well as hardware procurement, management, and maintenance. 

 Once a corporate perspective has been established, you may decide to work with a vendor for at least some part of an EDC solution. Even when the decision is to build rather than buy, a partnership with a vendor may provide a quicker or more reliable way to create a custom piece of the architecture. The vendor assessment process should address the categories shown in the Key Criteria box.

 A number of different technology architecture (hardware-software configurations) options are available for an EDC system. These include client-server, Web-enabled, and Web-based systems. System architecture should be selected to best fit a companys requirements for executing trial tasks as those requirements are defined in its needs analysis.The hybrid model, a combination of client-server and Web solutions, is currently popular because it allows investigators, coordinators, and clinical research associates to work unplugged and in batch mode, while providing Internet connectivity and giving sponsors potentially rapid access to data. 

Web-based or Web-enabled systems have many advantages, including ease of validation, deployment, and updating. Their most obvious limitations are Internet transmission speeds and barriers to connectivity. These should improve over time (as bandwidth increases and Internet access improves). As wireless technology becomes practical, it will let physicians, nurses, coordinators, and field-based clinical research professionals work online while still remaining unplugged. This has the potential to minimize the limitations they now experience because of the need to be connected while working with Web systems.

 to realize maximum value from EDC. Entering clinical data by EDC becomes powerful when that technology is integrated with other clinical research tools, such as a clinical data management (CDM) system, a laboratory data system, coding tools, a safety and adverse events reporting system, and drug supply, financial, and electronic regulatory submission (ERS) technology. 

 can be a particular obstacle to integration. They are often component-driven and can be home-grown solutions or third-party products. Prior-generation EDC products had to be retrofitted to existing internal technology architecture. In contrast, third-generation products are more flexible, parameter-driven applications and should be better able to integrate with a companys technology infrastructure. 

Even in our experience with more recent systems, for which integration is supposed to be no problem, we found that it takes a great deal of time and effort to move metadata and clinical data to and fromespecially tothe EDC system. Success in that effort requires addressing a tremendous number of details, from consistency in naming conventions to subject identification numbers. An integrated solution needs to deliver a consolidated high-level view of clinical trial information to a wide variety of stakeholders across the drug development enterprise. 

 Integration should become less difficult once industry approves the standards of the Clinical Data Interchange Standards Consortium, a group composed of software vendors and sponsors. CDISC has proposed a standard that will let vendors produce a transfer file that can be read by any CDISC-compliant system. The first version of the CDISC submission metadata model was released last year. The challenge of integration is to balance overall business processes, workflow and user requirements, and legacy source systems with the EDC product. 


Obtaining maximum value from EDC requires a new and more comprehensive approach to implementation. Top managers must direct a change management approach that addresses the entire spectrum of business processes in the clinical research division, and involves the major internal and external stakeholders. Those participating in the planning process need to learn about the options for EDC systems architecture, and determine which alternative appears likely to produce the best results. Careful consideration must be given to the build-or-buy decision with a view of corporate core competencies, and whether and how to use vendors. The task in vendor evaluation is to find the best fit among established EDC vendors and determine what relationship will provide the best obtainable level of comfort. 

Finally, in todays climate, knowledge management is a core competency for pharmaceutical companies. Maximizing value from an EDC system requires that it be integrated with existing and planned information systems to build an information-rich environment for business operations and decision-making. 


1.	Pharma 2005: An Industrial Revolution in R&D (PricewaterhouseCoopers LLP, 1301 Avenue of the Americas, New York, NY 10019) 1998.

2.	Electronic Data Capture: Survey 2000 (Association of Clinical Research Professionals, 1012 14th Street NW, Ste. 807, Washington, DC 20005). 

3.	Association of Clinical Research Professionals, ACRP White Paper on the FutureWhere We Are and Where Were Going, 

4.	Pharmaceutical R&D Statistical Sourcebook 2000 (Parexel, Rose Tree Corporate Center, 1400 N. Providence Rd., Ste. 2000, Media, PA 19063).


Assessing the needs of internal constituencies in the organization is a vital part of planning the change management process and should address the following issues.

	Financial and resources commitment, such as

	Costs for technology knowledge transfer and/or 	vendor services

	Cost of implementation, maintenance, etc.

	Risk profile and risk management, such as

	Technology integration objectives, such as

	Short- and long-term integration requirements

	Fit with broader technology strategy, such as

	Effect of other planned technologies in the division 	and company

SIDEBAR: Tufts Calculates Cost of New Drugs


The Tufts Center for the Study of Drug Development (Boston, MA) estimates that the average cost to develop a new prescription drug is $802 million.

The figure is the major conclusion of a recently completed study based on information obtained directly from research-based drug companies. The estimate accounts for the cost of failures, including research abandoned during development, and the opportunity costs of incurring R&D expenditures before earning any returns. 

Ten years ago, the average cost of bringing a new drug to market was $231 million. While costs have increased for all R&D phases, the increases are particularly acute in human clinical research. The inflation-adusted annual growth rate for capitalized clinical costs was more than five times that of preclinical R&D.

SIDEBAR: Key Criteria in Vendor Assessment


The vendor assessment process should address the following categories and criteria.

	Compliance with FDA requirements for documentation, 	training, security, and auditability

	User familiarity with industry regulations

	Annual contract vs. project-based approach

	Customization and optimization, including

Tremendous changes in the capabilities of EDC technology and the capacity of EDC vendors make electronic data capture a reliable tool for significant business advantage.

Realize Maximum Value When Implementing Electronic Data Capture

The beginning of the new year has brought the beginning of a new intensity to pharmaco-vigilance in the European Union. Partly for political reasons, and partly for technical reasons, the European Agency for the Evaluation of Medicinal Products has stepped up its activities in this area. The pressure is likely to increase as time goes by.

One of the political reasons for tougher controls is a desire at the highest levels of the European Commission to avoid being caught unaware. Embarrassment came close during 2001, when the President of the European Commission himself, Romano Prodi, felt obliged to issue a statement distancing the European regulatory system from the withdrawal of a medicine after side effects came to light. The product had not been authorized through the EU system, he pointed out, trying to deflect criticism over EU laxity. The national regulatory systems in the EU member states were responsible, the Commission insisted. But it could clearly see the risks of the European Union itself being dragged into yet another safety scandal. The EU had already endured the prolonged European bovine spongiform encephalopathy (mad cow) crisis, the 2001 foot-and-mouth outbreak (which was largely contained in the UK but threatened the whole of Europe), and the continuing arguments with the EU over the safety of genetically modified organisms.

To try to limit the scope for repetitions, there have been energetic efforts to clarify pharmacovigilance responsibilities at the national and EU level. After all, the European Commission knows well enough that if it tries too often to lay off the blame on member states, it will be accused of not doing its own job of making sure the EU rules are followed. And people in the European Commission still have vivid memories of the humiliations of the late 1990s, when criticism of its ineptitude led to the mass resignation of all 20 of the Commissioners who headed it up, and of the thenCommission President, Jacques Santer.

Another of the political reasons is that the Commission is aiming to prepare the way for abolishing the regular five-year renewal of marketing authorizations in Europe. It plans to introduce reforms to many aspects of the EU drug regulatory exercise over the coming years. And one of them is to eliminate the waste of time and effort in unnecessary administration. But to be able to win the battle against conservative forces that champion renewals as safeguards of patients, the Commission will have to provide plenty of reassurance. Tougher pharmacovigilance is one of the strongest weapons in that armoryand is being deployed with great vigor.

At the technical level, too, it is evident to the Commission and the EMEA that numerous minor improvements can be made to raise the quality and efficacy of pharmacovigilance, and thus enhance patient safety. So the new year has started with a new position paper in force on compliance with EU pharmaco-vigilance rules, and an action-packed program of work for the EMEA experts in this field, the Committee for Proprietary Medicinal Products (CPMP) Pharmacovigilance Working Party (PhVWP).


The pharmacovigilance working party program for 2002 has already firmly scheduled two-day meetings for most months of the year, and provides also for two additional three-day and two further one-day meetings. Some 50 cases are expected to arise from requests from the CPMP to contribute to a product assessment, and a similar number as a result of member states requests. There are expected to be 35 drafting/expert groups this year.

There is a forbidding list of CPMP guidance documents to be developed. A new guideline, aimed at competent authorities, is to be created on good pharmacovigilance practice (to be known as GVP). Other pharmacovigilance-related guidelines on the stocks, according to the draft work program, include an update of the note for guidance on the conduct of pharmacovigilance for centrally authorized productsboth to further strengthen pharmacovigilance and with a view to new therapies. An update is to be prepared for the crisis management plan regarding centrally authorized products for human use, to further improve provisions and procedures.

Further guidance is to be developed under the title principles of study system for safety monitoring, in the light of national experience. A concept paper will be developed on reporting adverse drug reactions from clinical trials to take account of the EU directive on good clinical practice. And under the new heading of Eudra-Vigilance, a paper is to be developed on predefined queries for signal generation, in collaboration with the joint subgroup of the Eudra-Vigilance telematics implementation grouplinking pharmacovigilance ever closer to electronic communications.

 a review of the current instructions on processing renewals in the centralized procedure.

 finalization of a standard operating procedure on urgent safety restrictions for medicinal products authorized through the mutual recognition procedure.

 finalization of a list of points-to-consider on xenogeneic cell therapy, following consultation with experts in the second quarter of the year (based on the concept paper adopted by the CPMP in November 2000).

 further work on the need for postmarketing data for the use of medicinal products during pregnancy (following the note for guidance adopted by the CPMP in June 2001).

 further work on the link between data and labeling in risk assessment of human reproductive and development toxicities (again following up on a June 2001 CPMP concept paper).

 a contribution to the note for guidance on the nonclinical documentation of medicinal products with well-established use being drafted by the CPMPs safety working party.

In light of the work in the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), the working party will make a contribution to maintenance of pharmacovigilance-relevant ICH recommendations, and will take part in ICH meetings. In particular, the working party will contribute to new ICH activities following the ICH meeting in Brussels in February 2002. In the framework of ongoing EU regulatory activities, it will contribute to the revision by a multidisciplinary working group of the guideline on the summary of product characteristics in the European Commissions December 1999 Notice to Applicants. With non-EU authorities, each meeting of the working group will include a regular videoconference and exchanges of urgent information with the U.S. Food and Drug Administration. There will be frequent liaison with regulators from the dozen countries now bidding to join the European Union. And with industry, there will be regular interaction with marketing authorization holders on product-related safety issues in form of data requests and oral clarifications as necessary, and interaction with industry associations at European level with regard to guidelines as necessary.

Reviews will also take place of the existing Standard Operating Procedure for the Review of CPMP Scientific Advice by the CPMP Pharmacovigilance Working Party, the Principles of Urgent Exchange of Important Information between the FDA and the PhVWP. And the PhVWP Work Program will be systematically updated at six-month intervals.

The working group has acquired additional status, too, in that its chairperson, vice-chairperson, and one representative per member state are reimbursed by the EMEA, as CPMP members and additional experts participating in the plenary meetings may also be (around 30 additional expert-days are expected to be reimbursed by the EMEA). This apparently insignificant detail reinforces the independence of the EMEA operation, making it less subject to the indirect psychological control of the member states, and thus adding another small push to the EU efforts to build a genuinely European regulatory system.


The new position paper on compliance with pharmacovigilance regulatory obligations (CPMP/PhVWP/1618/01) came into effect in January 2002. In its present shape, it sets out principles that the regulatory authorities in the member states are obliged to followand to require that marketing authorization holders also follow.

The rapid and effective identification and assessment of drug safety issues is dependent on early access to complete information, it states. And, it insists that this is fundamental to being able to protect public health and to take appropriate action swiftly when problems are identified. National authorities, it goes on, have an obligation to implement medicines legislation, and noncompliance with pharmacovigilance regulatory obligations could have a potentially serious public health impact.

The EUs pharmacovigilance regulatory obligations include not only the relevant sections of EU primary legislation (in the directives and regulations on pharmaceuticals) but also the range of guidelines. But what they boil down to for companies is the need for an appropriate system of pharmacovigilance to ensure responsibility for their products on the market and to ensure that appropriate action can be taken when necessary. This includes continuous availability of at least one appropriately qualified person responsible for pharmacovigilance within the European Economic Area (that is, the EU plus Norway, Iceland, and Liechtenstein). It establishes a system for the collection, preparation, and submission of expedited adverse drug reactions (ADRs) and periodic safety update reports to competent authorities.

The competent national authorities are required to monitor companies for compliance with pharmacovigilance regulatory obligations, and are obliged to exchange information in cases of noncompliance and take appropriate regulatory action. Any failure to immediately notify competent authorities of any change in the balance of risks and benefits of products may result in enforcement action, the guideline says. It should be noted that enforcement action is within the competency of individual member states, it states, leaving the onus for action firmly at the door of national authorities.

Competent authorities have to ensure that a system of pharmacovigilance is in place in each company whose products they authorize, through scrutiny of standard operating procedures and pharmacovigilance inspections. When marketing authorization applications are being assessed, national authorities should consider requesting documentation demonstrating that a system of pharmacovigilance is in place, the note says.

The guideline suggests a mixture of carrot and stick. The aim is to induce companies to undertake effective pharmacovigilance activityand also to make sure they are penalized for failure to do so. To ensure that companies comply with pharmacovigilance regulatory obligations and to facilitate compliance, competent authorities may conduct pharmacovigilance inspections, but, the guideline says, there should be collaboration between them to minimize duplication and maximize coverage. Inspections will be random and systematic, as well as targeted to companies suspected of being noncompliant, and the results will be routinely provided to the inspected company, which will be given the opportunity to comment on the findings. The results will be used to help companies improve compliance, it saysbut they may also be used as a basis for enforcement action.

When noncompliance is detected, the necessary action will be judged on a case-by-case basis. What action is taken will depend on the potential negative public health impact of non-compliance, but any instance of non-compliance may be referred for enforcement action. Regulatory options outlined by the guideline include 

 education and facilitation (companies may be informed of non-compliance and advised on how this can be remedied).

 inspection (noncompliant companies may be inspected to determine the extent of noncompliance and then reinspected to ensure that compliance is achieved).

 a formal warning from the competent authority.

 naming (making public a list of companies found to be seriously or persistently noncompliant).

 a formal caution in cases where it is admitted that a criminal offence has occurred.

 prosecution in cases of serious or persistent noncompliance (which may extend to company directors, managers, or the qualified person responsible for pharmacovigilance).The guidelineas the 2002 work program of the pharmacovigilance working group makes clearis going to be subject to continuing discussion on implementation issues. Already under way is a process of developing further guidance documents, in cooperation with an EMEA ad hoc meeting of GCP inspection services. So things are not going to get any more lax in Europe.

SIDEBAR: Regulatory Obligations for Pharmacovigilance


Each companys pharmacovigilance system should be capable of expedited reporting, periodic safety update reporting, responding to requests for information from competent authorities, handling of urgent safety restrictions and safety variations, continuous monitoring of the safety profile of authorized medicinal products and notifying competent authorities and health professionals of changes to the benefit/risk of products, meeting CPMP commitments for centralized marketing authorizations, and internal audit of the pharmacovigilance system. Pharmacovigilance data should be collated, and be accessible, at least at one point within the EEA.            

View from Brussels

To help protect patient safety and cut red tape, the European Union is working to create tougher standards of pharmacovigilance.

Tightening Up European Pharmacovigilance

I need to confess. I am addicted, obsessed, and there is no 12-step program to help me. What is the monkey on my back, you ask? My Palm Pilotmy external brain. My quest for efficiency coupled with growing dependence on that device, led me to discover that my job as a clinical research associate could be radically transformed and redesigned around the Palm Pilot platform and capabilities. Let me explain what would possess me to do that.

Paper pusherthats how the interviewer described being a clinical research associate (CRA). What he failed to tell me was that being a CRA also involved being a paper hauler. My first monitoring trip was a trial by fire, and I quickly developed a monitoring armamentarium. It included a carry-on suitcase and a soft-sided laptop bag weighing in at more than 20 pounds. My suitcase, of course, carried the personal essentials I needed for a weeks worth of traveling. My laptop bag overflowed with the following items:

	2-inch binder containing miscellaneous papers

	Pocket book of pertinent U.S. Food and Drug Administration (FDA) and the International Conference on Harmonisation (ICH) regulations and guidelines

	Monitoring kit that contained pens (black, blue, and red), highlighters, a variety of colors and sizes of Post-It Notes and Post-It Note Flags, stapler, staples, staple remover, and a variety of sizes of both paper clips and binder clips.

	Monitoring report, monitoring forms, and site-letter template

	Contact database containing all the communication with the site including emails and telephone conversations

	Subject and case report form (CRF) tracking files in both Microsoft (MS) Excel (Microsoft, Redmond, WA) and FileMaker Pro (FileMaker, Santa Clara, CA)

	Any additional work I might have brought along, to get done during my free time.The binder contained a variety of papers, including:

	Hard copies of subject and CRF tracking files

	Site correspondence copies (if not already sent ahead by Fed Ex)

	Maps and driving directions to and from the site, hotel, and airport

Who ever said that being on the road gives you no opportunity to exercise? Hauling that suitcase and huge computer bag around the United States built up muscle mass and left me with a feeling that there had to be a more efficient and less bulky way to travel. Palm Pilots are not just for subject diaries and dosing information. They can transform a monitors job, lessen the paperwork bulk, and save your lower back. Consider the following possibilities.

 such as Documents to Go can be used to transfer Microsoft Word, Excel, and PowerPoint files to documents that can be used and manipulated on the Palm Pilot or any other PDA that uses the Palm operating system (OS). You can transfer expense reports, monitoring forms, monitoring reports, site letters, subject enrollment tracking, and even site initiation slides to the Palm. You can manipulate them on the road and ready them for downloading and printing on the road or back in the home office. Site initiations and protocol summaries, requirements and study schedules can be put in PowerPoint slides to present at the site. 

 Laptop computer for creating, modifying, and presenting documents, spreadsheets, and presentations. 

 Adobe (Adobe Systems Incorporated, San Jose, CA) offers free Adobe Reader software for the Palm OS so that you can transfer any PDF (portable document format) files and view them on the Palm. Need a document translated into a PDF format? Adobe sells Adobe Acrobat to create PDFs from your own documents, or Web sites such as www.gohtm.com will convert your documents into PDF files for free.

 You can download current FDA and ICH documents from links found at www.fda.gov. Once downloaded and transferred, regulations and guidelines can be viewed and searched at any time on the Palm. You can choose which ones to carrynot just what is included in a pocket book. You can also transfer FDA guidance documents, internal SOPs, or any document in the PDF format.

 FDA and ICH Regulations pocket book and monitoring SOPs in binder.

 Using FileMaker Pro, I tracked subject enrollment, CRF collection, and payment to investigators, and maintained a site-contact database (all phone calls and emails). FileMaker Pro now offers a mobile software companion to version 5.0 and higher. Once you are back at the home office, you can synchronize the information you have added, deleted, or modified to update the main database.

MS Access is a popular database for subject, CRF, and document tracking. Like FileMaker Pro, this program has a software interface that translates MS Access into an easy-to-use database that is readable by Palm OS and can be updated during a hot sync.

 The need to carry a laptop computer for subject tracking and site contact maintenance and the need for hard copies of subject tracking in binder.

 was not always available to me to verify dosing or to learn about new pharmaceuticals. I quickly learned to carry my pocket version (which did not always contain all the drug references I needed). Now a PDA version (using Palm OS) of the 

 provides drug names, classes, and dosing. Several other vendors, including ePocrates, also supply drug dosing references (see table).

 At times, it would be handy to have an anatomy and physiology reference available just in case I had any questions. Several vendors offer anatomy and physiology references complete with text and pictures (see table).

 Pocket PDR and hard copies of reference material brought in notebook.

Driving directions, maps, and personal photos.

 Once you have software such as FireViewer Suite 6.0 that allows you to download and view images, photos, videos, and HTML files on your Palm, you can download driving directions and maps from www.mapquest.com or maps.yahoo.com.