Editors: David Machin, Simon Day, Sylvan Green (John Wiley & Sons, Ltd, 2004), 428 pages, hardcover, ISBN: 0471987875, 150

This varied book comprises 22 chapters written by 40 contributors, in addition to introductory and general information. The chapters are grouped into seven therapeutic divisions: cancer, cardiovascular, dentistry and maxillofacial, dermatology, psychiatry, reproductive health, and respiratory.

The editors devote a chapter to the history of clinical trials, high-lighting ways in which the practice of medicine in a range of chosen therapeutic areas has been influenced. Another chapter, dealing with general issues, covers Phases I to IV clinical trials, the designs of trials, randomized treatment allocation, endpoints, data monitoring, clinical trial reporting, data management, and analysis. Some of this information repeats in the other chapters.

The authors of the remaining 20 chapters have provided some very detailed information related to their specialities. The nature of the different diseases and how these have influenced the philosophy and design of research in the various therapeutic areas is especially enlightening. Those who enjoy reading about detailed medical science and the etiology of human disease will not be disappointed. The histories of clinical trials in areas such as breast cancer are covered. Also explained is why the skills of the investigator are far more important in surgical interventions than drug interventions.

Greater consideration could have been given to the fact that clinical research has undergone many changes in its fairly short history; in recent years, certainly in the developed world (especially the U.S., EU, CEE, and Japan), clinical trials have been subject to ever-increasing regulatory standards. Compliance with legally enforced international and national clinical trial regulations is required in most countries. The ethics of performing research on human subjects is rightly given very careful consideration, too, especially where trials may involve the substitution of effective therapy with inactive placebo, and should have been better reflected in the writing.

Some meaningful discussions on Good Clinical Practice (GCP), which is now a legal requirement in many countries, would also have benefitted readers. The philosophy and principles of GCP cover a very wide area involving compliance with ethical, scientific, and regulatory standards. A trial should only be performed in accordance with a written, approved protocol and undertaken by personnel who are suitably qualified. Freely given written consent should be obtained from every subject volunteer prior to participation, and the confidentiality of their records should be protected. Trial documentation should be accurate, verifiable and recoverable over a required time. The supply and usage of investigational products should comply with manufacturing and quality standards. There should be systems and procedures, especially regarding trial data, that assure the quality of every aspect of the trial. This is important to include for any textbook on clinical trials.

GCP regulations help to protect the rights, safety, and well-being of clinical trial subjects by requiring that trials are properly designed, conducted, recorded, and reported according to internationally recognized principles. Such regulations further protect public health by ensuring that the results of clinical trials are collected, recorded, and analyzed in accordance with those principles so that they can be audited and verified before being used to impact on public health. For example, the publication of a report that changes prescribing practice or as evidence to support applications to place medicines on the market. In the former case, we are reminded of the recent publicity surrounding the discredited research supposedly linking autism to the MMR vaccine.

GCP is an important first rule for all those wishing to initiate clinical trials, and as such it would have been helpful if this had been recognized and discussed. It is certainly true that within the EU, those who perform hospital-initiated and academic clinical trials after  May 2004 will be required to comply with these legally enforced standards. Due to the perceived differences in the standards which have previously applied to nonpharma-sponsored trials, the book misses an opportunity of helping those involved in clinical research to recognize the need for all individuals and organizations to comply with Good Clinical Practice.

In summary, Textbook of Clinical Trials is a very interesting book in which the editors could have supplied more up to date information, especially regarding the statutory standards for the planning, conducting, and reporting of clinical trials.

is the QA Director at the Crossland Consultancy, Swettenham Village, UK. Email: nigel.crossland@btinternet.com

Articles

Media Review

Editors: David Machin, Simon Day, Sylvan Green (John Wiley & Sons, Ltd, 2004), 428 pages, hardcover, ISBN: 0471987875, £150

Textbook of Clinical Trials

Digital dashboards will allow you to pilot your clinical trial from the captain's chair.

Does sitting on a plane get you thinking about life as a jet pilot? The hours I used to spend trying to keep my 747 from crashing into Lake Michigan in Microsoft's Flight Simulator had that effect on me. At the time, though, I was blind to parallels between flying jets and managing clinical trials.

On a transatlantic trip, a pilot and his or her co-pilot spend up to 12 hours in a small, essentially sealed room while a huge plane flies almost entirely on automatic functions. Yet, they must keep alert for any signs of danger or deviation from normal function or course, analyze the issue if it occurs, and respond quickly and effectively to it. These very specific needs are met by a cockpit display that manages almost every function of the plane. In fact, the cockpit display is really the same concept as a car dashboard, but more complex. But you already know all about car dashboards, don't you?

Monitoring an airplane is a sophisticated feat, but it comes down to principles that are applicable in monitoring any process, including clinical trials. Let's think about ways that we can classify airplane monitoring, and then see how these apply to clinical trial management.


I know some of the basic instruments of a 747, again through the magic of Flight Simulator. If you think about your glimpses of the cockpit of a 747 as you "deplane," there are a number of rows of switches surrounding the pilots, a variety of dials, and many computer screens. The old 747 had three people in the cockpit-two pilots and an engineer. They each monitored a separate set of mechanical and computer dials and displays. Today, the 747 is manned by only two pilots, and the displays are almost entirely computer screens. There are fewer monitoring displays, as well, since computers now monitor many engine-related functions.

The most important aspect of an airplane cockpit, or car dashboard, is the view. Operators need to monitor most, if not all, of the vital functions of highly complex, multifunctional vehicles without moving from their chairs.

The pilots have to keep their eyes on dozens of different functions throughout the plane, always mindful that any one failure could be dangerous for all aboard. These can be categorized into several different monitoring classes. First of all are the key indicators about the plane and its direction. This snapshot includes the altimeter, the airspeed indicator, and the horizon indicator.

While the stakes may not be quite as high as piloting a jet plane, running a clinical trial can be every bit as demanding. A large, multicenter clinical trial often involves tens or hundreds of people whose activities are coordinated across international borders in multiple languages. As with a plane, there are many different points of failure that can cause minor "discomfort," and many that can lead to significant damage or even complete disruption of the trial. These failure points can appear suddenly, or can be identified early as trends in the data. Wouldn't it be nice to have a "cockpit" for running your clinical trials? Well, the concept of a "digital dashboard" is currently quite popular in technology circles (and has been for at least five years), and is being incorporated broadly into software design. It is also finding its way into clinical trial software design.


You are probably already quite familiar with digital dashboards. The digital dashboard concept is based on the modular construction of Web pages. A digital dashboard Web page can be constructed with data and content obtained entirely from within one company, or from a dozen or more data sources scattered around the globe. When viewing the page, the users are unaware that they are not looking at one data source.

The most well known example of a digital dashboard is "My Yahoo." (http://my.yahoo.com--if you don't have one, it is worth it to set one up). This commercial dashboard allows a user to create a customized home screen that monitors many different concerns at once. One dash can monitor general and specific news, stock portfolios (with alerts for earning surprises, for example), weather, diet trackers, recipes, mortgage monitors, currency converters, personal address books, calendars, interactive maps, sport scores, email searches, local movies schedules, or even clinical trials. 

Many of these can be displayed on a single page with key information. Each alert or information item is typically linked to a more in-depth display of related data, often with the ability to expand well beyond the original data, using the Web. Many people have gravitated to this as their home page, customizing it to suit their needs. 

The management of a company may have a "digital dashboard" that provides front-end access to recent emails, voice messages, a calendar, search options for contacts, and many other personal functions. In addition there could be quarterly financial statements, the stock price and volume, the status of various projects, and production reports from factories. Thus, from a single seat the manager may be able to tell a great deal about the company's status.

As with the jet cockpit, the display may differ depending on the urgency of the information being displayed. For example, certain corporate information may be urgent in nature--a more than $1 fall in stock price; an urgent email; a delay of more than 30 days in a project. These events could trigger an alarm on the screen, which can be manifest in many ways--a red light, a flashing word, etc. The CEO would get a different set of alarms than the Chief Information Officer. They would share some alarms, but have others customized just for them.

Again, as in the jet, much of the data needs to be presented in a more detailed and complete fashion than an alarm, which is just an on-or-off binary state. In a jet these may be represented by analog indicators of pitch and yaw. Corporate dashboards, in turn, may be presented in tabular form, or as graphics--a pie chart, histogram, or point and line chart. Ideally, a mouse click on a particular graphic display of data would "drill down" to a more detailed level of information.

Finally, some of the digital dashboard would be the raw data itself--email messages or links to text documents. As with the jet's radio communications, sometimes the pilot needs to have direct access to the data itself. A summary alone will not suffice.Many software products are including the concept of a digital dashboard. Microsoft Outlook has a built-in digital dashboard that can be highly customized for individual users. In addition, many customized enterprise software programs are including digital dashboards for reporting on enterprise functions. A call center program might report waiting calls, time waiting, average waiting time, resolution status of last 24 hours, etc. As more and more data warehouses get built, the digital dashboard creates a perfect window to view aggregated business performance data. It allows managers to closely follow progress and develop forecasts for sales or production.

Again, as with the jet cockpit's systems view, business data is collected through business processes, and different analytic engines use the data to feed reporting engines. As in the jet cockpit, these reports can be binary on/off alarms or highly complex displays.

The ideal for the digital dashboard is for it to be the first thing that you look at each day: it's where you get your email, check your calendar, look at bulletins, identify problem areas for you and immediate action items, and dig into items of interest. It should also be a digital "destination" to which you return between meetings or phone calls and at the end of the day. In addition, it should synchronously communicate with your cell phone or PDA, sending along alerts automatically as they occur. As you can see, the digital dashboard can take on major significance and could be the most hotly sought-after "real estate" for software companies since the spreadsheet.


Clinical trial management is a perfect application for the digital dashboard. It is a complex and prolonged process with multiple participants taking many different roles. Investigator management occurs through communications and information collection, which is highly amenable to being incorporated into a dashboard. Furthermore, the clinical trial process has multiple steps where delays can occur, and the progress needs to be monitored against planned milestones. Clinical trial management systems have some rudimentary digital dashboards incorporated into some of them, but the sophisticated, "jet cockpit" digital dashboard hasn't yet been developed.

The digital dashboard for clinical trial management should be highly optimized for the individual role of the user. The project manager will have one view, while the data manager has another. One will be focused on milestones and budget, the other on data collection activities. Each of the participants from medical monitor to CRA would also have a view of the project through their dashboard. Many of the reports would be the same for all users--for example, typical office productivity tools like email, contacts, and calendar. In addition, some of the project information would be shared: project phone lists, recruitment forecasts, and many others.

The clinical trial digital dashboard would also be the window into the document repository for a clinical trial. One could envision a central repository where he/she might have the ability to read, modify, or even delete the document, all with a full audit trail.

The true ideal for a clinical trial dashboard doesn't come all that close to reality. Certainly, there are many that would claim the mantle of a clinical trial digital dashboard. However, the integration of all the different activities in a clinical trial, available to all involved, has not yet been realized. Like many good ideas, developing a robust clinical trial dashboard may take a convergence of workflow, new participants, technology empowerment, and process change.

A particularly interesting challenge in clinical trials is the "one investigator/many sponsor" problem. One investigator is likely to do clinical trials with several or even many sponsors. They don't want to have to use multiple digital dashboards for each trial, or even each sponsor. They would much prefer one dashboard that accommodated all of their workflow, from all of their sponsors. This would require the unlikely collaboration of all sponsors, or the emergence of one dominant design to work across sponsors. The most likely scenario is a dashboard standard that would accept "snap-in" modules from individual clinical trials or sponsors--the "killer application" still to come.			

Technology Viewpoint

Steering a Trial by the Seat of Your Pants

ongressional investigators are widening their probe of potential conflicts of interest between federal government employees and pharmaceutical and biotechnology companies. Allegations of questionable payments and cozy relationships first surfaced late last year; recently they have expanded from the National Institutes of Health (NIH) to include personnel at the Food and Drug Administration (FDA), too. Both agencies are tightening their rules governing outside consulting arrangements and are seeking more information on the extent of such activity, as additional federal watchdog agencies assess current policies and practices.

The fear is that further revelations of possibly unethical public-private relationships could lead to a ban on all outside consulting between government scientists and industry. Such a move could stymie collaboration vital to biomedical discovery and the development of new therapies, as well as deter leading scientists and clinicians from seeking government employment. Even without a total ban, heightened concerns about influence on government funding and regulatory decisions could chill interaction between sponsors and FDA and NIH staffers in the future. 

At the same time, the Department of Health and Human Services (HHS) released a final guidance on how clinical trial sponsors, IRBs (investigational review boards), and investigators should deal with potential financial conflicts of interest. The policy outlines actions that should be taken to reduce the possibility that any financial interests could harm research participants [see sidebar]. 

For the past six months, the Senate Appropriations Subcommittee on Labor, Health and Human Services, and Education, along with the House Energy and Commerce Committee, have been investigating allegations of financial conflicts of interest (COI) of NIH employees. The Senate panel opened the debate with a January hearing on COI charges, which committee leaders feared could undermine public support for biomedical research and NIH funding. The House E&C panel also launched a series of hearings on NIH employee consulting activities, calling on Congress' General Accounting Office (GAO) to examine the financial relationships of NIH employees with drug companies, and also the NIH procedures for preventing conflicts. The committee recently requested that the HHS Office of the Inspector General (OIG) review FDA employee outside activity requests for the last five years.  

This request to the OIG arose from a May hearing before the House E&C Oversight and Investigations subcommittee that closely examined certain industry payments to NIH and FDA scientists. The panel, chaired by Rep. James Greenwood (R-PA), questioned a $40,000 award from the University of Pittsburgh to former National Cancer Institute (NCI) Director Richard Klausner that could appear as a payoff for help in settling a researcher's lawsuit against the university (an unproven allegation).  

Greenwood's panel also examined consulting arrangements of Lance Liotta, chief of the NCI pathology laboratory, and Emanuel Petricoin, a senior investigator at FDA's Office of Cellular Tissue and Gene Therapy in the Center for Biologics Evaluation and Research (CBER). Both had agency approval to work with a San Francisco-based company, Biospect. But with the spotlight intensifying on COI issues, NCI and FDA recently advised termination of the activ-ity. Petricoin also declined a previously accepted paid speaking invitation from ImClone and Bristol-Myers Squibb. 

In response, FDA Acting Commissioner Lester Crawford launched an agency-wide inquiry into the extent of payments by pharmaceutical and biotech companies to FDA staffers. The review failed to unearth further questionable staff activities, but Crawford announced additional oversight procedures to ensure continued compliance. FDA will: 

 Require CBER directors to review and approve employees ' requests to participate in outside activities - instead of delegating such reviews to lower level managers 

 Expand the number of staffers required to file declarations of financial holdings

 Conduct an annual review of outside activities and financial disclosures

 Issue a staff guide on outside activities to clarify the rules. 

NIH Director Elias Zerhouni also has requested that all NIH employees report the financial details of any paid consulting agreements with pharma or biotech firms over the past five years. This includes high-level NIH scientists who previously were exempt from public disclosure of outside income sources. 

Zerhouni's action builds on the findings of a blue-ribbon Committee on Conflict of Interest Policies, which the NIH chief established in January to investigate possible COI charges due to employees receiving consulting fees and stock options from drug companies. The panel, co-chaired by National Academy of Sciences President Bruce Alberts and Lockheed Martin executive Norman Augustine, unveiled its recommendations in May. Instead of banning all consulting with industry, the panel proposed to limit such activity by senior managers and NIH officials with influence on grants and funding decisions.1 Most NIH staff scientists and clinicians could continue to engage in conflict-free collaborative research that is limited in time (under 400 hours a year) and level of compensation. Stock payments are out, as well as membership on the boards of research institutes or biotech companies.  

The uncovered proliferation of public-private interactions between NIH and FDA employees and outside organi-zations reflects the intentional relaxation of rules in the mid-1990s under NIH Director Harold Varmus. In testimony before the House Investigations Sub-committee in May, Varmus acknowl-edged his efforts to boost pay scales for NIH scientists and to lift restrictions on outside consulting activities to attract more prominent researchers to the agency and to promote good science.  

Varmus emphasized that it is important for NIH intramural researchers to interact with industry and academia in order to fully exploit new biomedical discoveries, and to recruit and retain top scientists. At the same time, Varmus acknowledged that "the rules of engagement need to be more explicit and frequently revisited." He supported "reasonable limits" on the number of hours and amount of compensation that NIH employees receive from outside activity, and curbs on such activity by senior NIH personnel responsible for awarding grants. 

Zerhouni defended the "outstanding" work of his blue ribbon panel and maintained that its proposed limitations on consulting activity were "not trivial." He believes that it is important for most of NIH's 6000 scientists to be able to interact with outside researchers in order to understand the latest research developments in pharmaceutical and biotech companies, noting that a ban on all such activity would be "catastrophic in the long term."  

While it appears that Congress will hold off on completely curbing all outside relationships of NIH and FDA researchers, new disclosure requirements and closer review of employee interactions with industry may make government employment less attractive for prominent researchers with attractive offers from the private sector. And higher hurdles may deter pharma and biotech companies from entering into cooperative agreements with federal agencies. Although it is important to maintain public respect for NIH and FDA research activities, excessive oversight could have a dampening effect on valuable scientific collaboration. 

www.nih.gov/about/ethics_COI_panelreport.htm

View from Washington

FDA and NIH investigate staff relationships with industry to eliminate any outside influence on regulatory decisions and clinical trial procedures.

Congress, Agencies Probe Conflicts of Interest

What would a sponsor think if he were suddenly requested to provide (yet again) the following information on a trial? Believe it or not, this is just an abbreviated list: 

Full title of the trial; sponsor's protocol code number, name, or abbreviated title of the trial; sponsor identity, details and history of the investigational medicinal products being tested or used as comparator (including pharmaceutical form, route of administration, all strengths to be used, provenance of active substance); details of placebo; details of the medical condition on which the trial is focused; main and secondary objectives; principal inclusion and exclusion criteria; primary endpoints, scope and phase of the trial; design of the trial, sites, dosing and duration; population of trial subjects and details; principal and coordinating investigators; central technical facilities; duties subcontracted; trial monitoring facilities; and ethics committee and protocol details. 

It's not just a hypothesis. In Europe it is the new reality. New guidance has just emerged about the functioning of the embryonic EudraCT database, which is intended to provide an overview of clinical trials being conducted in the European Union. This new tool is intended to allow national authorities to compile information on a standardized basis, to communicate with one another and with the European Medicines Agency, to improve oversight of trials and investigational product development, and to enhance protection of subjects. 

The system applies to any clinical trial with a site in any of the EU member states-which now number 25 with the inclusion of many central and eastern European and Baltic states in May. The information will cover the content, commencement, and termination of trials and inspections, and will be linked within the Eudravigilance database of reports of suspected unexpected serious adverse reactions reported during clinical trials for investigational medicinal products. EudraCT will also send a message to the competent authorities whenever an entry is made in the database indicating that a trial has been terminated or suspended for safety reasons. It will automatically notify member states when a trial is terminated or suspended anywhere  in the EU. 

A unique EudraCT number will identify each clinical trial, irrespective of the number of sites or member states involved. This number must be included in the submission of the request for the trial to the competent authorities and ethics committees, and used on any amendments or the end of trial report, as well as on suspected unexpected serious adverse reactions reports. 

Each investigational medicinal product will also be identifiable through the Eudravigilance product dictionary, reflecting the requirements for identification of products through their development cycle. Where several active substances are included in one product, these should be individually identified. Where a product that is being used in the trial has a marketing authorization in the EU, the tradename and the marketing authorization number will suffice. Flow diagrams showing the process of sponsor registration and submission of data elements are detailed in the specification and design documents in the system, as well as validation of these and entry into the database by the competent authorities. But the database will not contain individual personal information relating to clinical trial subjects/patients. "Personal data should be protected in accordance with the provisions of Good Clinical Practice," the guidelines say, another challenge for sponsors. 

Each clinical trial needs to be clearly identified in the database before the competent authority assesses it (and before the competent authority provides written authorization for the trial, or takes the decision that there are no grounds for nonacceptance). This is to ensure that the database is a complete database and can fulfill its objectives. In particular, it is necessary to ensure proper reporting and review of suspected unexpected serious adverse reactions.  

The requirements imposed on the clinical trial sponsor are numerous. The sponsor is required to notify the competent authority of the end of the trial, or of its early termination. The sponsor is responsible for the accuracy of data submitted to the competent authorities.  

Sponsors will have to register with the system in advance-both for security reasons, to protect the system from unauthorized access, and to ensure authentication of the information submitted, by establishing the sponsor as the authentic source of information for that company and in the context of this database. And failure by the sponsor to submit accurate or complete information may be a reason to consider the request submitted to conduct a clinical trial to be invalid. 

But in a bid to present the new scheme as a time-saver rather than a time-waster, the new guidance points out that the data required is a subset of the data required in any case for the request for authorization, so it can also be used for submissions to the competent authorities and the Ethics Committees. 

"To facilitate the implementation of the database, and to enable search and reporting functions, data will be entered in English whenever possible," the guidance points out. "Where feasible," dropdown menus and picklists may be provided in the official languages of the EU, it adds-but since there are now 19 of these official languages, feasibility is going to be a heavily conditioning factor in the equation. Maltese, for instance, is one of the new official languages of the EU since its May enlargement, but this is spoken by only 300,000 people in the world. In fact, the EU has found it impossible to recruit enough translators and interpreters to fulfill its new task of putting everything into Maltese-and the same problem is likely to emerge with other new official languages spoken by less than 2 million people, such as Estonian, Slovenian, or Latvian, which have also now acquired official European Union status. 

All it needs is for the current wave of lobbying for other European languages to win official status to make the sponsor's life complete: how about Catalan or Welsh? Both of these are spoken by as many or more people as many of the EU's new official languages, and the new European Parliament, being elected in mid-June, is sure to put forward plenty of sympathetic arguments in this direction once it gets going later this year. 

Meanwhile, all those still trying to keep a grip on Europe's shifting reality need to take on board a challenge. The CPMP-the key committee of the European Medicines Agency in London-is dead, but has immediately re-emerged with a new membership and a new name. 

The reason is that part of the new EU pharmaceutical legislation1 came into force on 20 May 2004-including the administrative changes in the work of the agency. (The remaining parts will be enacted on 20 November 2005.) In fact, the new rules have also changed the name of the agency, so now it will be officially known by its unofficial title, the European Medicines Agency. Absurdly, however, it will continue to use the acronym "EMEA"-which denoted the European Medicines Evaluation Agency, itself a transmogrification from the original title of the European Agency for the Evaluation of Medicines!  

The old Committee for Proprietary Medicinal Products, the Agency's senior scientific body for human medicines, has been abolished. Instead it now has a Committee for Medicinal Products for Human Use, to be known as CHMP. The first meeting of the CHMP took place at the beginning of June, with its modified membership. 

Now it has 27 members (and the same number of alternates-as substitutes are termed in Brussels): one from each of the now 25 member states, plus Iceland and Norway. The reduction from two members to one member per member state is intended to boost the professionalism of the new committee, making nomination more related to personal expertise than mere ceremony. And because the new rules have come into force just days after Europe grew from 15 to 25 member states, this meeting was also the first time that members from the 10 new member states were fully included in the Committee's work.  

But not everything has changed: the new Committee started its three-year term by electing Daniel Brasseur as its chairman and Eric Abadie as its vice-chairman-two key figures in the now-extinct CPMP. 

The agency's new 33-member Management Board has also just met, and gave its approval to the new CHMP. It also elected a new chairman, Professor Hannes Wahlroos, director-general of the Finnish National Agency for Medicines. The Management Board has also been slimmed down by the new EU rules: it now has one representative from each of the 25 member states, two representatives of the European Parliament, and two representatives of the European Commission. The revised legislation also adds for the first time two consumer representatives and two representatives of health care professionals (one for doctors and one for veterinarians). 

Other changes that came into effect in May include a reinforced role for the agency in giving scientific advice to companies, cooperation with the WHO in giving opinions for the use of medicines outside the EU, and opinions on the compassionate use of unapproved medicines. The agency will be given a stronger role in providing information to patients and the public, including a mandate to develop a database of all medicines approved in the European Union ("EuroPharm"). And small and medium-sized companies can also obtain greater administrative and scientific support. 

When the rest of the package comes into effect in November 2005, there will be changes on conditional approvals and fast-track reviews, in addition to an increase in the scope of the centralized procedure. 

Meanwhile, the agency is moving rapidly towards its own redefined world. It has recently launched a consultation exercise on its plans for the future-set out in a discussion document entitled "The European Medicines Agency Road Map to 2010: Preparing the Ground for the Future." The paper outlines the agency's strategy to turn itself into "one of the world's foremost regulatory authorities for medicinal products." It plans to be "public health oriented, science-driven and transparent in the way it operates." And its ambition is to meet that familiar two-fold challenge of both protecting patients and encouraging research.  

At the same time, the plan tries to find a realistic way of operating in an enlarging Europe. Behind all the weary management-speak about implementing visions and establishing networks of excellence, there is a hard-headed recognition that it is going to be difficult to function in effective partnership when more than 40 national agencies are involved-as EU strategy already foresees. All the more so when the size of the countries and their sophistication and experience in drug regulation varies between Germany, the United Kingdom, or Denmark at one extreme, and Bulgaria, Bosnia-Herzegovina, or Albania at the other. 

It may be tough for the clinical trials community around the world to follow what's happening in the agency, but it's pretty tough too for the agency as it tries to react to the new demands imposed on it by politics, geography, science, and history.  

1. EU pharmaceutical legislation Regulation (EC) No 726/2004, published on 30 April 2004 (OJ 136, 30.4.2004, p. 1). 

View from Brussels

To present the new scheme as a time-saver rather than a time-waster, the new guidance points out that the data required is a subset of the data required in any case for the request authorization.

Asking the Impossible of European Understanding?

 For those who want all of the advantages of both IVRS and eDiaries , there is the cell phone mDiary

Vocel (San Diego, CA) has come up with an innovative, inclusive solution for electronic clinical trials: combine the benefits of IVRS and PDAs with a flip-style cellular phone. 			

As with the standard interactive voice-response systems, the mDiary(tm) is connected to a database server, so all responses go directly to the server. (They also go to a secure United States Postal Service server; a USPS "electronic postmark" appears at the end of every session.) As with PDAs, the LCD screen allows for a full-color display with illustrations, text, analog scales, and multiple-choice questions and well as input fields. Questions can be changed mid-study, and each compliant response gives the user another 10 minutes of personal phone time.  

Vocel's adverse event log was not able to blend all of its two parents' benefits without adding in a few liabilities. The phones aren't free, and many subjects who already have a cell phone may not enjoy having a second one. The phone is only as good as the network using it, which could be trouble for people in rural and heavily urban areas. 

Vocel also offers SAT prep questions, games, and email cell phone services.			

Fit over two dozen languages on one small label, thanks to a ripping good idea from Clinical Systems, Inc. 

Clinical Systems, Inc. (Garden City, NY) offers a sophisticated suite of labeling aids, from text layout to blank stocks clients can fill out themselves. To solve a pernicious problem of global labels, they took a page from page-a-day calendars. 

Most large trials will need labels in more than one language, but the expense and time of having separate print runs for each different type of label is frustrating. Also, an unused Spanish-labeled container can't be shipped to a French-speaking trial without a label change.  

Enter ClinBook, a multipage label that gets printed in all a trial's languages, like VCR instructions in a minute book that is adhered to a pill package like a sticker. All of the pages in this Rosetta Stone, however, are perforated. By tearing out all but the appropriate trial site's language, one label becomes customized for two dozen or more separate languages. Or, leave them all on, and the bottle speaks to billions in their native tongues.  

ClinBooks can include options such as four-color printing, scratch-off unblinding labels, and durable plastic label covers, and come in sizes and die cuts appropriate for any dispenser or bottle. The entire process is cGMP compliant.			

 Radio and newspaper ads work for subject recruitment , but not as well as taking a peek at a million files

Provisio Inc. (Nashville, TN) realizes that for every CRO scouring far and wide for a particular subject, there is a person matching that exact description on file in a doctor's office, ignored. Its iTrials service tries to introduce the potential subject with the questing sponsor. 			

A big part of any trial is the subject recruitment phase, increasingly focused on media advertising. The iTrials method takes a step in the opposite direction, relying on a web of PPOs, pharmacies, and private-practice physicians to bring potential subjects to 700 private-practice offices containing over 323,000 doctors. Provisio has a relationship with The Independent Physician Association of America which allows the start-up to search participating doctors' files for possible matches with a sponsor's upcoming trial. The end result: millions of patient records viewable to see if any would make for good subject material. 

Thanks to a partnership with The Independent Practice Association of America, Provisio has a foot in the door of over a third of all IPAs nationwide.			

News

Vocel's mDiary, Clinical Systems, Inc.'s ClinBook, and Provisio Inc.'s iTrials

eShowcase

n December 1998, NASA launched a spacecraft designed to enter a fixed orbit around the planet Mars. The Climate Orbiter reached Mars in late 1999 and, early in the morning of 23 September, fired its main engine to commence maneuvers into the target orbit. As the craft passed behind Mars, everything seemed normal.  

The spacecraft never re-emerged from behind the planet. NASA instigated an investigation and concluded that two teams involved in the project had each used different measurement units in navigation calculations; one team had used imperial units while the other used the metric system. This practice had resulted in data being passed between the teams and used without the necessary conversions. As a result, a multimillion dollar spacecraft was lost due to a simple data transfer issue. 

A similar event happened during the testing of computer systems destined for use as part of a clinical trial. Fortunately, although it was essentially the same problem, it did not have the same impact as the NASA incident. A blood glucose reading and other data was going to be collected from a number of subjects, and the data stored on a server located in Europe. That would then be transferred, in an encrypted ASCII format, to another server in the United States where it was to be used for analysis.  

An issue arose upon the commencement of system testing. The glucose reading for the subjects was being stored on the server in Europe as mmol/L, while the analysis software was expecting the readings to be measured as mg/dl. The protocol had not specified which unit was to be used. The fix was simple, luckily, and a few days later the problem was resolved.  

These two example, albeit at either ends of the scale in terms of their impact, illustrate the potential cost of errors in data transfers. Within the pharmaceutical industry, one organization is working hard to improve the mechanisms available for the transfer of clinical data. The Clinical Data Interchange Standards Consortium (CDISC), a nonprofit organization, has been working over the last four years on the development of standards to support clinical data interchange. 

One of the CDISC standards is the Operational Data Model (ODM), and this article is intended as a primer for those who would like an introduction to the model. The article tries not to delve into great technical detail, either about the ODM itself or the technical aspects of the model's implementation. Hopefully, it provides just enough information to understand the concepts. 

The ODM has its roots in 1999, when work first commenced on what resulted in a first draft of the standard, Draft 0.8, issued in March 2000. Since then, several versions have been released for review-in October 2000, Version 1.0 was released. November 2001 saw the review release of Version 1.1. The formal release of Version 1.1 occurred in April 2002. The most recent version, Review Version 1.2, was released for comment in July 2003 and was released for implementation in January 2004. 			

The ODM has taken some time to evolve into the model we see today. The slow rate of progress in developing the ODM, and the other three CDISC models, is a criticism often levelled at CDISC as an organization. This seems somewhat unfair. The subject domain is a complex one, and the wide-ranging interests of the parties involved make achieving consensus difficult and time-consuming. 

The CDISC data models are designed to support the end-to-end data flow within clinical trials, from the operational database through analysis to regulatory submission. The role of the ODM is to facilitate the movement of clinical data collected from multiple acquisition sources to an operational database, but it also has application in the subsequent exchange and archiving of such data. 			

The model has been designed to be flexible enough to allow data from a variety of sources, such as electronic or paper case report forms, electronic Patient Diaries, laboratory data, and others, while also allowing for data to be passed to and from data stores. 

The ODM specification defines the format of an ODM file as containing the ODM root element with four main subelements (see Figure 1). 

The Study element, used to detail basic study information such as study name, and to define the MetaData for the study. 

The AdminData element, used to hold user attributes such as locations and signatures for those participating in the trial. These items are used for audit trail functionality, for example. 

The ReferenceData, used to detail data used in the interpretation of clinical data. An example of such data is laboratory normal ranges.

The ClinicalData section, used to hold the data collected as part of the trial.

At the start of this article, two scenarios where data was transferred and interpreted incorrectly were described. In these scenarios, the users had misinterpreted the data. They had the data but did not fully understand how that information should be interpreted; in other words, they had the data but not the metadata. Data are the actual values while metadata is the description of that data. 

The metadata held within the study section is central to the concepts behind the ODM, as it defines the structures and interpretation for the data that is to be collected as part the specific clinical protocol. This inherent ability within the ODM to define the structures provides the means by which we can avoid error scenarios such as those described at the start of this article. Since the ODM specification details the format and ordering of elements, a computer can check the validity of not only an ODM but also, by using the metadata, the data within the ODM.  

To illustrate the use and power of the ODM, consider the following simplified example of the data collection process employed during a clinical trial. An investigator recruits a patient and proceeds to collect some basic demographic data. This data is written on a paper case report form (CRF), and then entered via a computer for onward transmission into a database located on the servers of a CRO. The CRO is then requested to pass the data to a third party. 

The data collected is nothing more complex than the site number at which the subjects were recruited, their sex, weight, and height, and a unique subject identifier, as illustrated by an extract from the paper CRF shown in Figure 2. 

This data could be passed in a number of ways. For example, it might become a Comma Separated Variable (CSV) file-similar to that used to import data into Microsoft Excel. Figure 3 depicts the various data flows. 

Figure 4 shows an example of a single entry that encoded within such a CSV file. The data is for subject 12 recruited at study center 5. Subject 12 is a male, weight 87.2 Kg and is 156 cm tall. Note that the position of each of the data items is assumed, as are the units for each field, a practice that can lead to errors, as has already been discussed. 

Alternatively, the ODM could be employed to transport the data. Figure 5 shows extracts from an equivalent file for the same data as within the CSV file. As can been seen in the figure, the ODM file is composed of the metadata and the ClinicalData elements. The metadata element contains the definition of the paper CRF within the StudyEvent, Form, and Item elements. The subject data is held within corresponding elements within the ClinicalData.

One immediately apparent issue is the verbosity of XML; the relative size of the CSV and ODM files is quite marked by comparison. However, it would normally be the case that each ODM file would not contain the metadata definitions. The ODM specification allows ODM files to refer to others, and this allows for the metadata to be held within a single ODM file referred to by all others. This results in most ODM files only holding data within the ClinicalData section. 	

	By adopting the ODM, pharmaceutical companies can benefit in a number of ways to improve their clinical development processes and reduce their costs. Data quality is a major consideration for all involved within the clinical trials process and, as already discussed, the ability to define the data content and the meaning of that data content can help in the battle to reduce errors when data is transferred. 			

Whatever the format used in exchanging data, be it CSV, ODM, or some other format, the costs of setting up and operating the exchange of clinical data have to be met. Costs will typically be incurred for activities such as: 

The definition of the specification that defines the format

Programming effort to implement the support for the format

Testing to ensure that the interface works

Importing , exporting , and checking during the trial

Archiving the data at the end of the trial. 

These costs can escalate rapidly if the work is repeated for each trial or for each organization involved in the trial. This is especially true when the costs of programming and testing are taken into account, as these are expensive activities. By employing a standard mechanism, an organization can avoid the additional costs created by additional formats. Further benefits can be achieved once a standard mechanism is in place. By employing this mechanism on each subsequent trial, an organization will increase the savings with each trial undertaken once the costs of the initial investment has been met.  

In addition to the cost savings that standards bring, the use of the standard provides for operational flexibility. As adoption increases within the industry, and organizations adopt the standard and associated tools, companies will enjoy the freedom to work with a greater number of suppliers or customers and choose from toolsets that support the standard. 			

The ODM is a powerful mechanism for the transfer of clinical data. However, with any power there is always the ability to abuse it. So, some words of caution.  			

The first recommendation for any organization wishing to use the ODM is to stop and think: think about how you wish to use it across an organization, not just within a single trial. How many times have we seen various technology pilots that work but do not scale to encompass the organization as a whole? 

Simple issues like conventions for trial identifiers, site identifiers, and location identifiers need to be considered. All that needs to happen is for the same identifier to be used to denote two different studies, and the data for both appear to come from the same study! None of this is rocket science; it simply requires a little thought and organization, and yes, maybe a Standard Operating Procedure or two. The same caution needs to be applied to the names of items used to hold the clinical data, as the names may need to take into account the processes undertaken during the analysis phase. 

An old adage, but one worth remembering, is Keep It Simple. It is recommended that, rather than placing all metadata and data into a single file, organizations use a number of files. Consideration should be given to file structures, and the best way of working given the toolsets being deployed. 			

The ODM permits a single file to contain some or all of the elements. It will almost certainly be true that by putting everything into a single file, that file will become large and complex. It is true that the ODM file will be processed by a tool running on a large and powerful computer, but well-organized data can only assist the general logistics of a trial. 

It is recommended that you keep metadata separate from clinical data, and always refer to the metadata. It is worth remembering that the metadata represents the protocol, so it is necessary to keep it under configuration control as well as all of the other files. 

It should also be remembered that the ODM is a means of representing data and not the means by which the data is sent-it is simply a file. Therefore the file may well need to be encrypted prior to transmission depending on where and how it is being sent, to ensure the data stays confidential.  

The use of the ODM within any computer system will have an impact on the validation undertaken. The cornerstones of the FDA's policy on computerized systems used within clinical trials are data quality and integrity. The mechanisms for data transfer used within a system, whatever the mechanism employed, should be one area that should be closely scrutinized. 			

The danger with any import or export function is that any flaw in the process affects all subsequent processing based upon the data. There is little point spending significant amounts of money and effort in a data collection process that produces high-quality data only to have the whole exercise invalidated by a function that fails to export the data correctly. Any risk analysis undertaken on a system as part of a validation exercise should take such an eventuality into account. 

Feature Article

Think about how you wish to use ODM across an organization, not just within a single trial. All that needs to happen is for the same identifier to be used to denote two different studies and the data for both appear to come from the same study!

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