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Web-based ESA applications provide an infrastructure that can improve the success rate of outsourcing relationships.

Enterprise Services Automation Software

Meet the EAB

Moving between the UK and Switzerland, and between academia and industry has given Editorial Advisory Board member and statistician Stephen Senn a well-rounded view of pharmaceutical development.

Stephen Senn

Mutual understanding of roles and responsibilities across the boundary between IT and clinical operations allows both departments to function more effectively.


Information technology has been the driving force behind the remarkable productivity improvements of the past decade. These gains are largely attributable to the fact that the technology has become more fully featured and easier to use, which has resulted in greater user proficiency. There is still, however, a significant gap in the relationship between the developers and the users of information technology, particularly in the clinical trials arena. Indeed, IT and clinical operations are both highly technical disciplines, the workings of which are not easily accessible to the uninitiated. Yet observing some rather simple rules of engagement can bridge the gap. This article looks at a number of areas in which communication bridges can improve interdepartmental relationships:

	Training outside an employees area of responsibility

Clinical operations and IT have their own distinct languages and abbreviations. Clinical researchers can speak to each other meaningfully using such abbreviations as GCP, NDA, and IND. IT professionals know what one another mean when they speak of VPN, GUI, and bandwidth (see Glossary). Although this kind of verbal shorthand helps facilitate intradepartmental communication, it often poses an impediment to effective interdepartmental dialogue. When clinical operations and IT interact, they should limit their use of technical jargon and abbreviations. For example, saying that access to the host computer is slow because the new program transmits much more information across the connections is infinitely more comprehensible to clinical personnel than saying Your VPN does not provide sufficient bandwidth to support the new GUI. Although the simpler explanation may not be technically precise, it conveys the general sense of the problem. 

The more clearly and simply such issues are explained, the better the interaction between the clinical and IT worlds. 


In the era of specialization, the value of generalists is often underestimated. But a few well-placed corporate positions, filled by persons with a wide scope of knowledge, can be extremely helpful. This is especially true in the no-mans-land between IT and operations. Here a business analyst or IT liaison reporting either to IT or to operations can create and maintain a dialogue between the two departments and objectively assess issues from both perspectives. 

Such liaison is particularly crucial when a new piece of software needs to be developed. Knowledge of both the best business practices and the difficulties of software development allows the two departments to evaluate the impact of new software long before the first line of code is written. A generalist with a foot in each camp can communicate to operations some of the constraints that developers face as they attempt to resolve conflicting requirements or work with limited resources. In this role, the IT liaison serves as a translator familiar with the language, culture, and idiosyncrasies of the respective parties.


In clinical settings, although training is routine and essential to success, all too often training opportunities are limited to areas for which the employee is responsible. But informal cross-training between departments can be extremely beneficial. That is not to say a contract research associate should be trained to do C++ programming or that a senior programmer should know the normal pediatric ranges for all blood chemistry analytes. 

Informal monthly seminars, alternating between clinical and IT issues and conducted by nonsupervisory personnel, can serve as forums for exchanging vital information. Topics might include logistics issues (such as sample transport), software testing and validation, construction of case report forms, and how the Web works. Issues that are normal routine to people who deal with them every day can be steeped in mystery for those who do not. Informal seminars can provide valuable insights for those involved in interdepartmental communiation.

Pairing people in IT and clinical operations for a day can also yield significant benefits. The IT person could spend the morning with a clinical person, learning firsthand about operations challenges. The roles would be reversed in the afternoon, so the operations person could observe the IT person at work. This type of cross-training helps create an invaluable corporate culture of teamwork.


When a clinical operations department requires a modification to some software application, they typically submit a formal request in writing to IT. In turn IT proceeds to process the request, as time allows, without realizing that operations is often unaware of the status or progress of the request. Inevitably that leads to frustration. The solution to this type of situation lies in communication between departments. Clinical operations needs to state its need for regular updates on the status of the modification and the anticipated implementation date. Most software development enterprises have some type of bug-tracking software that allows them to enter detailed information about a change request and to track it each step of the wayfrom user requirements and functional specifications through code development, peer review of code, unit testing, system testing, user acceptance testing, and any other steps. Such tracking software often indicates the current owner of the change and the anticipated release date.

IT can generate weekly reports with a small subset of informationfor example, change request description, current owner, status, anticipated implementation date, and IT contactto keep clinical operations apprised of progress. The information can be put on an intranet site, where all employees have immediate access to it. Weekly reports may not accelerate the process, but they can dispel uncertainty by projecting an implementation date.


Software developers need a clear understanding of the way an application will be used in the real world. When clinical operations needs a new application, or revisions to software currently in use, it is customary for IT and clinical operations to schedule a series of joint meetings to determine user requirements. To ensure that the software works the way operations intends, the two departments need a continuing dialogue. If IT develops a finished application based on only the initial meetings, the software may not work as needed. 

Before laying down actual code, developers often perform what is called a proof-of-concept design. This involves making a prototype of the software simply to ensure that the design is feasible and will function as required. At this stage, operations personnel should be brought back into the loop so they can test the application. 

Even though bugs may still exist and not all features have been included, operations staff members can get a sense of whether the finished product will meet their needs. For large projects, several such meetings should take place during the software development cycle. Although the frequent interaction may lengthen the timeline for the project, when the software is delivered, user acceptance is virtually guaranteed. 


One of the most difficult issues confronting IT is the ripple effect of software modifications. A simple change requested by operations might affect many of the other modules, windows, or functions in the system. A change to the way a clinical report form displays data on a computer screen, for example, can affect every other place in the system that uses the same data elements. So a seemingly simple change can actually be a difficult IT assignment in a large, complex system. In these situations, the business analyst must assess all of the operational and software impacts. Otherwise, the development process will be slowed, and additional modifications may be required after the software has been implemented.

 Given the urgency of change requests and the limited time and resources most IT departments have to fulfill them, IT and operations should hold regular meetings to discuss priorities and deadlines. IT needs to understand what is causing problems in operations, and operations needs to understand the difficulties involved in completing certain projects. As a team, they can negotiate aggressive but realistic deadlines. Once they set priorities, they should adhere to them, thereby averting midstream changes in focus that can be wrenching and costly to everyone involved.,P>In the data-intensive business of clinical trials, an optimum relationship between IT and operations is vital to deliver the kind of results that are critical to the success of a clinical trial. That means learning to speak one anothers language in simplified, nontechnical terms. It means designating an interdepartmental liaison person knowledgeable in both clinical operations and software development. It means cross-training to foster understanding and appreciation of one anothers roles in the organization. It calls for tracking and communicating the status of IT projects and using prototypes to ensure that finished software meets users expectations. And it means evaluating the impact of changes on the overall system. Both the clinical operations and IT departments will function more smoothly and efficiently when understanding and communication bridge the gap that too often separates them.

  A term used to reference the volume of data that can be passed back and forth between systems or computers. 56K (a typical modem bandwidth) would pass about one quarter of the volume (and therefore speed) of a 256K frame relay line. Its comparable to lanes on a freewaymore cars can travel on an eight-lane freeway than a two-lane freeway. At rush hour it makes a huge difference.


 programming  C++ evolved from C. An object-oriented programming language (as opposed to a linear programming language like COBOL or BASIC) that is used to create many client-server applications. 


  graphical user interface. The part of the software application a user actually sees on the monitor and works with to enter data or perform certain functions.

  local area network. Networks that connect computers that are physically close (normally in the same building). 


  virtual private network. Hardware and software that allows computers to be linked via the Internet (public access), but have security and protection that emulates a direct connection (private access). 


  wide area networks. Networks that connect computers that are physically distant. 


Bridging the Gap Between IT and Clinical Operations

Wireless computing may be the way of the future, but several obstacles currently prevent us from achieving it.


Although the Internet spawned the new economy, its been said that wireless computing will spawn the new new economy. With the degree of travel and the high demand for remote information access that exists in clinical trials, mobile computing provides the timeliest mechanism for accessing, and in some cases capturing, clinical trial data. Two categories of wireless platforms are poised to affect clinical trials: cellular wide-area data networks and wireless local-area networks (WLAN).

The vision of mobile computing is easily imagined today; however, significant challenges impede progress toward ubiquitous wireless computing in clinical trials. Consider six of these challenges: high, perhaps inflated, expectations; still waiting for an indispensible application; dead spots in cellular coverage; unsettled standards; insecure airwaves; and a still-uncertain technological future.


The acceptance of Internet technologies into clinical trials with the great promise of cleaner data faster, real-time trial visibility, and disintermediated processes makes the notion of wireless computing in clinical trials readily imaginable. We already understand the efficiencies promised by Internet technologies. Therefore, wireless = Internet + mobility. Our expectations for new technologies have been set by the impact of the Internet.

But having such heady expectations for wireless clinical trial automation is more likely a liability than a strength. The wild success of the Internet grew from our extraordinarily low expectations for the technology. In 1994, we surfed the Web using our Mosaic browsers with minimal expectations. The quirky and often homegrown sites we visited were just for fun. At that time none of us anticipated e-commerce transactions to the tune of billions of dollars. 

Geography also affects expectations. While Americans wait for cable modems and DSL to fulfill their need for high-speed browsing, Europeans tend to be more interested in bandwidth for their mobile phones. In Europe, the number of mobile phone users is more than double that of home Internet users.

Solid business drivers support extending existing infrastructures to provide mobile access to clinical trial data. However, the limited wireless data infrastructure demands that expectations be carefully managed. Rapidly evolving technology, a fragmented device base, sparse network coverage, uncertain standards efforts, and very limited device capabilities make wireless clinical information systems challenging.


Successful technology platforms have historically benefited from the existence of an application that generated such tremendous demand that it justified the existence of the entire platform. The IBM PC had Lotus 1-2-3 and word processing, the Apple Macintosh had desktop publishing, and the Web had commerce.

Wireless computing in clinical trials has not found its indispensable applicationyet. Mobile voice technology is ubiquitous, but significant mobile data communication is still the exception rather than the rule. So, is there real demand for wireless applications in clinical trials today, or do we just hear noise generated by the marketing engines of a few technology pioneers? Acknowledging the fact that no indispensable application is readily apparent, it is fair to say that some obvious pockets of demand do exist today. For instance, wireless electronic subject diaries and the wireless delivery of clinical trial portal content are in use today.


Cellular data networks provide true mobilitysort of.  Nevertheless, cellular network coverage deficiencies create reliability issues, as weve all experienced with voice coverage. Reliability is the foundation upon which any communication technologys ubiquity is built. In the United States, POTSplain old telephone serviceand its ever-present dial tone has set the expectation level. A recent Consumer Reports survey found that only half of the respondents were completely or very satisfied with their cell phone service.

Testing coverage and reliability a priori is neither simple nor easy, especially when users might be moving in and out of coverage areas. This significantly complicates wireless electronic diary deployment. What assumptions have been made about coverage, and what contingencies accommodate those without coverage? Expectation management is critical, because a real-time data collection system cannot deliver on its promise without adequate network coverage. Subjects outside covered areas may need to use a different system that requires separate processes and procedures. 

Further complicating matters, those networks with the best coverage also tend to be the slowest. Many of the most popular data service networks run at 9600 bps, extraordinarily limited by wired standards.


Growth of the wired Internet benefited greatly from relatively stable standards. Competing and often incompatible standards have limited the effectiveness of wireless data applications. Differences between U.S. and European cellular technologies complicate global rollouts. Furthermore, a technology standard cannot assume survival; many will not become mainstream.

Bluetooth, for example, is in danger of becoming the ISDN of the wireless worldirrelevant by the time it arrives in any practical way. Bluetooth is a short-range standard that provides always-on connectivity for PDA-laptop synchronization, wireless Web surfing, and downloading music. But support for the standard seems to be waning in light of the significant popularity of the WLAN (802.11b) standard. Microsoft and Intel have both recently expressed concern and limited their support for Bluetooth.

Many argue that 802.11b WLANs provide all the functionality offered by Bluetooth at greater speeds and distances. 802.11b provides a 100- to 300-foot bubble of wireless access, operating at performance levels similar to wired networks. WLAN technology promises immediate impact by running the same applications supported in the wired world. The advantages that Bluetooth enjoys in small, low-powered devices will go away with the newer implementations of 802.11b.

Deploying WLANs in Phase 1 units seems to create obvious value. Assuming no restrictions on wireless deployments (as there are likely to be in a hospital), WLANs enable laptops to be positioned where they are most useful within the clinic, without necessitating a wired network connection. Internet-based electronic data capture (EDC) systems and data reporting tools can be fully accessible anywhere within the clinic. 


Security issues are paramount in wireless information systems, because most wireless technologies involve broadcasting signals over the airwaves. Because broadcast signals can be intercepted by anyone, the trick is to secure the privacy of messages through encryption, as well as to authenticate the parties exchanging information. Securing wireless data is possible, but not simple.

WAP (Wireless Application Protocol) is the most common protocol used to access Internet-based information via a wireless platform. The wireless equivalent of TCP/I, WTLS (Wireless Transport Layer Security) secures WAP communications and is the functional equivalent of SSL (Secure Socket Layer) in the wired world. Unfortunately, although WTLS and SSL provide similar functionality, they are incompatible with one another.

These incompatible security models create a vulnerability commonly referred to as the WAP gap. WAP communications begin in the wireless world, but eventually reach the wired Internet to access Web applications. Because WTLS and SSL are incompatible, the gateway bridging the wireless and wired world must convert the incoming message from WTLS to SSL. At the time of the conversion, the message is left unencrypted, in plain text, for a microsecondthe WAP gapjust long enough to cause serious concerns among security experts. Many companies consider the vulnerability negligible. For example, Ameritrade permits WAP-based trading, while others like Fidelity consider the WAP gap an unacceptable risk. 

The 802.11b WLANs have also been plagued by security shortcomings. 802.11b uses WEP (Wired Equivalent Privacy) to ensure that intruders are not intercepting network traffic. Earlier this year, UC Berkeley and others published theoretical shortcomings in WEP. Just recently, theory became reality when Airsnort was released on the Internet. Airsnort enables nearly anyone with some technical savvy to detect, intercept, and decrypt traffic, including passwords, on 802.11b networks. Hackers could easily intercept information while outside of a building, because only access to the bubble is required.

Ironically, the same companies spending millions to protect their networks from the Internet have WLANs installed, creating significant exposure. In fact, the Gartner Group stated that while 50% of all organizations currently plan to deploy WLANs, 20% of large enterprises already have rogue WLANs in place. Rogue WLANs are installed by non-IT users, often have no security enabled at all, and are typically connected to other corporate networks.

WLAN deployments are expected to grow rapidly over the next five years, and their availability will have an impact on clinical trials. To make them secure, however, requires additional layers of security. Virtual private networks (VPNs) are one mechanism for improving security, and Cisco has announced products that add additional security to WLANs, making them appropriate for use with sensitive information. WLANs alone, without additional security measures deployed, should not be considered for use with sensitive or regulated information.


Of course, the future of clinical trials includes wireless information systems. Of that there is little doubt. The timing, however, is open to debate. There are many technologies either available today or on the horizon that will play a role in the future wireless IT infrastructure.

Better interoperability and higher bandwidth will solve many of the current limitations with wireless applications. New standards like 3G (3rd Generation), or even 2.5G, wireless have been developed to provide enough bandwidth for an interactive multimedia wireless experience. These high-speed wireless data services will enable a new generation of applications to be deployed on every imaginable type of device. But 3G has experienced significant delays. In fact, skeptics suspect that the delays indicate that the technology, in its current state, doesnt work. The skeptics claim the high-speed 3G devices will experience battery life problems and become unbearably hot. Much like high-speed wired Internet access for the home, it appears that high-speed wireless data communications will be slow to arrive.

Security will continue to be a major concern. While WAP and other wireless Web technologies have been slower to catch on in the United States and Europe, Japans i-Mode has over 25 million subscribers and is growing at 1.3 million new users per month. This makes i-Mode the worlds most successful wireless data service by a wide margin. Interestingly, viruses, spam, and Trojan horses, security issues that target only wired systems in the United States have hit the i-Mode network. Consider this foreshadowing.The future might even find a home for wireless PKI (public key infrastructure). Security experts widely consider PKI critical to deploying secure mobile applications. However, a quick survey finds many PKI companies faltering. The adoption, even in the wired world, just isnt there.


Although wireless computing may spawn the new new economy, Ive never been completely convinced that any technology thats considered new new will succeed in the clinical trial technology market. Maybe not-too-old technology is as leading-edge as we can hope for. Newness aside, wireless computing appears to represent the next great technology frontier for clinical trials. 

Think of wireless data today as the Web in 1994. Although our low expectations of the Web allowed the technology to evolve satisfactorily, our expectations for over-hyped wireless computing outstrip reality by such a large measure that frustration is inevitable. On the other hand, those of you running clinical trials who crave the latest technology will find wireless applications deployed today. 

Proceed with caution, though, and acknowledge the limitations of todays solutions. WLANs offer mobility within the clinic, but additional security measures must be applied. Cellular data networks offer true mobility for electronic diaries and Web portalbased information access, but beware of gaps in coverage and limitations in bandwidth and processing power.             

Inside IT

Wireless Data: Challenges in the New New Economy

Investigators are sometimes eager to open a subjects blinding code when they perceive a medical emergency. Informing investigators about expected adverse events can forestall these requests.


According to the ICH Guideline for Good Clinical Practice (4.7), the investigator should ensure that the code is broken only in accordance with the protocol. If the trial is blinded, the investigator should promptly document and explain to the sponsor any premature unblinding . . . .

 Situations that might warrant breaking the code are usually defined in the protocol (a serious adverse event, for example). Still, some investigators understand breaking the blind as a compulsory step to be followed with any serious adverse event, even if knowledge of the study drug is not relevant to the treatment of the adverse event. 

Examining an event that occurred in Spain suggests some ways to avoid unnecessary code-breaking. An investigator phoned the sponsor asking to open a subjects blinding code. The subject was in a double-blind Phase 2 study for the treatment of benign prostatic hyperplasia. The therapies being compared were two different doses of a new alpha blocker, a marketed alpha blocker, and placebo.

 I was in my office when the phone rang. It was Dr. X, who sounded as though he were in a state of great panic.

Subject MJO received the first dose four hours ago, and now he is having postural hypotension, said Dr. X. His blood pressure is dropping every second, and now it is 101/65. I need to know immediately what drug he is taking, he demanded. Is there any particular treatment for this event?

The standard treatment as for any postural hypotension, I said. There is no need to open the blind.

My response did not calm the doctors anxious demands. Well, I need to know the drug anyway. In the event of a cardiac arrest, the emergency personnel will need to know all the medications he was taking. And even if theres no emergency, Id like to tell the subject what he was taking, he said firmly. 

I will need to discuss this with the project manager in charge of the study, I said, but Dr. X was not to be delayed.

Look, his blood pressure is dropping to 91/60! he said. He is sick and dizzy. There is no time for discussionIm opening the code.

I did not argue further. The blinding code was opened, and revealed the standard treatment. Dr. X administered intravenous fluids, as for any postural hypotension. One hour later, the subject had recovered.

 At my office here in the UK, I got a voice mail message from the CRA. I thought it was crazy to break the code, but by then it was too late; the code was broken. What could I do?


Why did this investigator want to open the blind even though there was no antidote for the new drug and the expected adverse reaction would have to be treated like any other alpha blocker postural hypotension? Perhaps the investigator had his doubts about the study drug. Sometimes it is hard for a clinical research associate to explain the meaning of events to a project manager who comes from a different medical/scientific culture. The difference in perspective can lead to misunderstanding, investigator lack of confidence, and project manager misinterpretation of an adverse event. The investigator might have been embarrassed about referring the subject to another doctor without knowing the study treatment. Not knowing the name of the drug that caused the adverse event might have made the investigator feel uneasy in front of the subject.

Investigators have a legitimate reason to open the blind when the study drug is likely to have a significant effect on clinical management of the subject, as in the case of a serious adverse event. Without adequate information about what adverse events they might expect, investigators could believe that any adverse event could become serious.

Consequences of breaking the blind for one subject


Whether or not a medical emergency warrants breaking the blind, unblinding has several consequences.

	Subsequent assessment of that subject may be affected by the investigators (or sponsor staffs) knowledge of the treatment received. 

	The subject will generally be included in an intent-to-treat analysis, but will usually be excluded from the evaluable subject or protocol-compliant analysis, even if the subject continues and completes the study normally. Therefore, by breaking the blind we lose data.

	If the open blinding disclosure code is not quickly forwarded to the data manager, the subjects data may be inappropriately included in evaluable subject analyses.

	Finally, blocking is used to try to ensure that each site has subjects on all study treatments. When the randomization code is based on small blocks, breaking the blind for one subject may reveal information about the treatment of other subjects. The study cited in this article used a block size of four, with one subject in each block receiving each treatment. Knowing what our unblinded subject was receiving tells everyone that the other subjects in the block were receiving something else. (Sponsors are often secretive about the block size to make this detective work harder for investigators.)


Taking a few precautions in advance can decrease the likelihood of anxious calls like the one in our example. 

First, provide information to the investigators about the adverse events that might occur and the treatment required. If you refresh this information at every opportunity, you will improve your investigators confidence in their ability to handle expected adverse reactions without opening the blind.

If a medical emergency does arise, urge the investigators to make every effort to consult the studys clinical manager before opening the blinding code.

In case a clinical trial subject is treated by physicians other than the investigator, the investigator should describe on the clinical records the treatment to follow in case of an expected adverse reaction. This might stop physicians not familiar with the clinical study from requesting permission to break the blind.


1. Guideline for Good Clinical Practice, International Conference on Harmonisation, Federal Register 62 (901) 2569125709 (9 May 1997; also available from EMEA, 7 Westferry Circus, Canary Wharf, London E14 4HB, UK, or www.eudra.org/humandocs/PDFs/ICH/013595en.pdf).

2. Sally Hollis and Fiona Campbell, What is Meant by Intention to Treat Analysis? Survey of Published Randomised Controlled Trials, 

3. K.F. Schulz et al., Blinding and Exclusions after Allocation in Randomised Controlled Trials: Survey of Published Parallel Group Trials in Obstetrics and Gynaecology, 

MD, is supervisor clinical research associate with Pfizer Global Research and Development, Ave. Europa, 20-B Parque Empresarial La Moraleja, 28108 Alcobendas, Madrid, Spain, +34 91 490 9479, fax +34 91 490 9712, e-mail: Eduardo_Ayala@sandwich.pfizer.com.

MD, is senior director, Pfizer Global Research and Development, Sandwich, United Kingdom.

Investigators are sometimes eager to open a subject?s blinding code when they perceive a medical emergency. Informing investigators about expected adverse events can forestall these requests.

Educating Investigators to Understand When to Break the Blind

Efforts to develop anti-terrorism treatments and to fully include women in studies will both affect clinical research.


The September 11 attack on New Yorks World Trade Center and the Pentagon in Washington dramatically revised the political agenda in the nations capital. The new focus on national defense and international affairs at the White House and Congress greatly reduced interest in domestic health policy issues, including stem cell research, the cost of new medicines, and clinical trial oversight. 

One result of the terrorist attack was the cancellation of a September 12 briefing to mark the official release of the final report of the National Bioethics Advisory Commission (bioethics.gov/ human/overvol1.html). In August, the Commission issued recommendations that call for a new federal agency to ensure the rights and safety of human research participants. Now Congress is even less likely to address the issue, unless new scandals involving human research protections erupt.

The nations campaign to thwart terrorism is generating new efforts to protect the public against biological warfare, which could increase investment in research on new therapies to treat and prevent infectious diseases. There has been considerable talk in recent years of the need to develop new therapies and diagnostic tests in this area, but a sense of immediacy has been missing from the debate, comments BIO (Biotechnology Industry Organization) president Carl Feldbaum. Now he expects a much greater commitment of both public and private resources to develop vaccines and therapies against a biological attack, as well as to treat infectious diseases and injuries related to combat. 

President Bush touched on this issue in announcing that his new Office of Homeland Security will oversee counter-bioterrorism initiatives of government agencies. The Department of Health and Human Services (HHS) previously announced a five-year plan on this subject. The program involves increased surveillance by the Centers for Disease Control and Prevention (CDC), more support for research by the National Institutes of Health (NIH), and efficient FDA oversight. 

At FDA, Andrea Meyerhoff in the Office of Science Coordination & Communications is coordinating agency efforts with CDC to expand the National Pharmaceutical Stockpile and to facilitate approval of critical antibiotics, vaccines and other treatments. Center for Drug Evaluation and Research (CDER) director Janet Woodcock has assigned anti-bioterrorism initiatives involving drugs to the new Office of Pediatric Drug Development & Special Initiatives. This is directed by Diane Murphy, who has been in charge of the review of anti-infective products as head of CDERs Office of Drug Evaluation IV. One assignment for FDA and CDC is to ensure the physical security of pathogenic agents and toxins in research facilities. HHS has asked pharmaceutical and biotech companies to examine what reagents and products they use that could interest terrorists, as well as what technologies could be used to defend against biological or chemical attacks.

These initiatives would gain more support from a proposal developed by Senators Edward Kennedy (Democrat, Massachusetts) and Bill Frist (Republican, Tennessee). They want the White House to provide some $1.5 billion to increase R&D on new therapeutics and diagnostics, fund government purchase of vaccines and antibiotics, improve regulatory review of bioterrorism products, and expand the capacity of local health agencies and hospitals to deal with health emergencies. 


One task for FDA is to clarify its policy for conducting clinical trials of therapies for treating exposure to toxic substances. The agency issued a proposed rule in October 1999 on Evidence Needed to Demonstrate Efficacy of New Drugs for Use Against Lethal or Permanently Disabling Toxic Substances When Efficacy Studies in Humans Ethically Cannot Be Conducted. The policy calls for FDA to have authority to approve treatments for exposure to deadly chemical, biological, and nuclear substances based on animal studies to establish efficacy, in addition to safety studies in humans. FDA recognizes that requiring human efficacy studies could block the development of such therapies, but that waiting until a toxic accident occurs to test such products is not very practical. 

Debate over how to test protective therapies arose during the Persian Gulf War when the Department of Defense (DOD) sought to administer an experimental anti-botulinum vaccine to soldiers, but failed to seek informed consent. This led FDA to address the broader issue of whether it is ever ethical to expose volunteers to toxic substances to test the efficacy of a protective therapyand, if not, to determine what criteria FDA can use to approve a therapy for an indication that has not been fully tested in humans. 

FDAs policy staff is working on a final proposal that aims to clarify how sponsors may develop and test new products to treat infectious diseases as well as protect against biological weapons. CDER expanded labeling for Bayers Cipro (ciprofloxacin) as a treatment for exposure to anthrax based on primate studies showing reduced mortality following exposure to anthrax spores for the treatment group. FDA is determining what study data is needed to label other drugs for protection against biological threats. It also is developing a process to permit the use of investigational drugs in case of such an attack. 


Feldbaum and other industry leaders have met with HHS secretary Tommy Thompson and with DOD officials to discuss what manufacturers can do and are doing in these areas. DOD is particularly interested in learning more about products developed for the commercial market that could be important for the military, such as new wound-healing treatments. DOD and BIO may sponsor a joint conference next year to discuss military needs for biomedical therapies, vaccines, antidotes, and other treatments.

The new focus on bioterrorism also may stimulate investment in the relatively moribund U.S. vaccine industry. Feldbaum observes that vaccine development needs increased public funding, an FDA fast-track review process, and liability relief, particularly for small companies. Although DOD has supported studies of vaccines for AIDS and other diseases, biomedical research has not been a high-profile activity of the huge military establishment. Now Feldbaum detects a seismic shift in DOD interest in what academic institutions and private companies are doing, which could lead to more funding for large-scale clinical trials. Although some observers argue that the danger of biological warfare has been exaggerated, others note that supporting R&D for new products to treat infectious diseases could benefit public health.


In addition to encouraging development of new anti-terrorism treatments, the special initiatives staff in CDERs new pediatrics office is heading efforts to clarify FDA policy on trials that involve drugs used during pregnancy. FDA and HHS recently awarded contracts to two biomedical research centers to study appropriate doses for hypertension drugs (lobetol and atenolol) in pregnant women. The aim is to improve labeling of medicines commonly used during pregnancy. The research also will give investigators experience in conducting clinical trials involving pregnant women. That could support FDAs program to ensure that new medical products are tested and labeled for women as well as men. FDA has eliminated earlier rules that limited the overall participation of women in clinical research. In 1993 the agency formally revoked a 1977 policy that restricted the enrollment of most women of childbearing potential in Phase 1 or Phase 2 trials. Recent policies require that sponsors include analysis of demographic subgroupssuch as men and womenin new drug applications (NDAs). Another rule permits FDA to put an investigational new drug on clinical hold if the sponsor excludes women from studies of critical therapies. 

Members of Congress want to know if these policy changes have altered research practices. In August, Congresss General Accounting Office (GAO) issued a report indicating a good deal of progress since its last study in 1992: Women accounted for more than half (52%) of clinical study participants from 1998 to 2000. However, the report noted that womens participation still varied greatly in early trials, and was noticeably low in small safety studies. This is an important shortcoming, GAO analysts state, because early studies provide toxicity and dosing information that shape the design of later, larger trials. 

GAO also questions whether sponsors and FDA reviewers analyze data sufficiently to assess possible differences in mens and womens responses to drug dosing. Of the 36 NDAs that GAO examined, about one-third of the summary documents lacked full safety and efficacy data by sex. And almost 40% of IND annual reports lacked the required demographic information. GAO advised FDA to improve its system for tracking women in clinical trials and for monitoring whether medical officers adequately assess sex differences. 

FDAs own review of this issue by its Office of Special Health Issues (OSHI) similarly found that women participate in clinical trials in numbers equal to men, including early study phases, and that gender-specific pharmacokinetic information is included on most product labeling. That report, however, acknowledges some variation in the way medical reviewers in CDERs drug evaluation offices present and discuss sex-related issues. CDER officials say they hope to see more consistent analysis of study data in the coming year as reviewers begin to use a new Clinical Review Template. The template includes a section on mens and womens exposure to the investigational product. CDER also offers its staffers an online course on sex differences and policies regarding participation of women in clinical studies. Another FDA initiative is to develop an agencywide clinical trials demographic database designed to help FDA monitor inclusion of women and other demographic groups in clinical trials and to assess any impact on safety and efficacy. 

Overall, the agency will be looking to ensure equitable enrollment of women in early safety studies and consistent analysis of sex demographic data in study summaries and annual reports. Even though none of the NDAs that the GAO examined found clinical differences of sufficient significance to warrant special dosing or labeling for women, GAO notes that data in many cases indicated higher drug concentrations in women. At a time of increased concern about pharmacokinetic and pharmacodynamic differences between patients and great interest in individualization of treatment, policymakers want sponsors to fully analyze what may look like unimportant treatment             

View from Washington

Bioterrorism and Research Policy

A high-level group explores ways to support EU pharmaceutical industry research without too much cost to the EU health agencies that pay for medicines.


A top-level European think tank is urging an increase in national and European Union public research funds devoted to clinical research and development, and efforts to promote bilateral and multilateral research cooperation. It is also suggesting the development of a European clinical research agenda that would identify public health priorities for fundamental research on new medicinal therapies needed in both the industrialized and the developing world.

Think tanks are, of course, ten a penny, and their ideas do not necessarily translate into policy. But this think tank is different. It consists of 10 of the most influential politicians, officials, and pharmaceutical industry executives in Europe. And its initial thinking stands a better chance than most of becoming policy.

This is the group that has styled itself the G-10. A grandiose title. But its pretensions are in line with the grandiosity of its chosen title. Its fuller title is the high-level group on innovation and provision of medicines. It was set up by the European Commission early in 2001 to find new answers to perennial problems of European pharmaceutical industry competitiveness. It is due to present a report by April 2002 to European Commission President Romano Prodi with recommendations on how to support EU pharmaceutical industry research without too much cost to EU health agencies that pay for medicines.

It is co-chaired by two European Commissioners: Erkki Liikanen, who is responsible for industry affairs, and David Byrne, who is in charge of health and consumer protection. And its other members include health and industry ministers from the major EU member states, the CEO of Sanofi-Synthlabo, and the European president of GlaxoSmithKline.


After some six months of preparatory work, the group has just produced a consultation document that outlines its thinking on how to deal with the challenges of supporting drug development without bankrupting the social security agencies that pay for most medicines in Europe. The documents scope ranges widelybut what it has to say about clinical research is particularly revealing of the groups agenda.

Examine for a moment the propositions that head up this article. An increase in national and European Union public research funds devoted to clinical research and development, for instance. A good thing, of course, to have more funds plowed into clinical research and developmentalthough it tends to fly in the face of the received wisdom that most clinical research and development for new medicines is conducted within the private sector.

Or look at the idea of efforts to promote bilateral and multilateral research cooperation. Cooperation is, naturally, a good thing in principle. But if it is successful, it will raise questions about which of the bilateral or multilateral partners will have the rights to exploit the results.

The real clues, however, lie in the passage that refers to the development of a European clinical research agenda, which would identify public health priorities for fundamental research on new medicinal therapies needed in the industrialized and in the developing world. Curiosity is immediately provoked about who would set this European clinical research agenda, about what the criteria would be to identify public health priorities for fundamental research, and about the source of the omniscience to decide in advance on which are the new medicinal therapies needed in the industrialized and in the developing world. 

Everyone who has ever worked in clinical research will instantly recognize the tell-tale signs of latent dirigisme in this formulation. And everyone who has ever brushed against European politicsand particularly European Union politics with respect to medicineswill immediately perceive that a series of trade-offs are already in the making in the way the subject is being approached.


The clues are, in fact, even more obvious than that. How can a think tank dealing with competitiveness be co-chaired in such a way that the man responsible for industrial affairs sits alongside the man responsible for public health and consumer affairs in Europe? In some respects their interests may overlapbut in others they are diametrically opposed. Developing new drugs costs money. The money comes from profits on drug salesand in simple terms, the more the profit, the more research can be done. That is the obvious way to promote industry competitiveness, and the innovation it depends on. But the interests of public health and consumer affairs, by contrast, are to have high-quality drugs available as widely and as cheaply as possible.

There are more clues. The membership of the G-10 also includes senior figures from the generic and nonprescription medicines industrieswhose interests hardly overlap with those of research-based companies. It also includes distinguished representatives of patients groups and social security agencieswho tend to argue for access to medicines at the lowest possible price.

The reality of the G-10 group is that it is already a compromise in its composition, and is almost certain to come up with a compromise in its recommendations. The compromise was forged far back in the history of the European Union. When the EU was set up, the member states decided what the EU would deal with, and what they would continue to deal with themselves. They agreed to pool responsibility for industrial policy, for instance, and they decided to remove all barriers to cross-border trade within the EU borders. But they decided to keep for themselves responsibility for some sensitive national matterssuch as taxation, and the way that medicines are paid for and reimbursed. More than forty years on, this remains the case. So while there may be pressure to boost the pharmaceutical industrys research potential as a matter of industrial policy, this always runs headlong into national pressures to keep down the price of drugs and control the amount that social security agencies have to pay out for them in reimbursement or copayment.

Spain, France, Greece, and many others of the current 15 EU member states continue to impose tough price and reimbursement controls on medicines. And inevitably, therefore, the EU doctrine of free movement of goods across borders tends to drive a parallel market in medicines. Wholesalers go to the countries with the toughest price controls, buy up large quantities of internationally successful medicines there, then ship them to the countries with less stringent controls (such as Germany or the UK). They sell them to retailers there at less than the local pricebut high enough to be able to make a profit themselves and to allow local retailers a cut, too. The net result is a reduction in the revenues of the companies producing those successful medicinesand a reduction in the profits available for research.

Countries like Spain, France, and Greece have no problem with this arrangement. They still get their medicinesincluding the internationally successful onesat low prices. But, as the European research-based industry has long argued, this compromises the overall European revenues that provide for the development of internationally successful medicines, which are generally developed and produced by companies in the countries with higher prices.


Alongside this stream of European confusion runs another that is equally confused: private sector research is wasteful, inefficient, too costly, and unfocused. It is a view often championed by European consumer organizations, and frequently supported by social security agencies. It also often overlaps some of the strong negative prejudices in Europe about the pharmaceutical industry as a parasitemaking extravagant profits from the sick, ignoring the real interests of patients. More recently, and to a large extent because of drug industry mismanagement of its relations with developing countries, it has also been widely perceived as a callous exploiter of profitable markets that turns its back on product development for poorer markets where real needs remain unmet. How much more rational it would be, runs this argument, to eliminate the wasteful self-indulgence and duplication of some drug companies research programs, and direct those programs from some more altruistic notion of what is really necessary.

This is why the G-10 group has a very mixed membership. It is the latest in a long series of EU attempts to square a circle, to reconcile innovation with low costs. This is why it offers hope of backing for innovation with one hand, then takes it away with the other in the name of health-care economies.


There are other examples of these mixed motives in other aspects of the G-10 consultation paper. Systems for postmarketing surveillance should be reviewed to ensure that coordinated processes are in place in each of the member states to gather data on adverse events and patient safety, it says. And it urges that the European Commission should provide core funding for European patient groups to enable them to participate independently in the debate and decision-making on health matters at a European level. 

The paper also suggests that the EU should develop a coherent policy in the field of clinical research aimed at improving its qualitywith a clear presumption that at present there are some deficiencies in its quality. Specifically, it urges organizing larger and more targeted clinical trials on a European scale, focussing on innovativeness criteria and based on all relevant results (including negative). The industry may have been its own worst enemy in allowing a situation to emerge where it is presumed to be excluding negative data from trial results (as the recent furor over publication of results has demonstrated so compellingly). The consequences are now evident. Even in the eyes of such a distinguished high-level group, the starting point is that industry is not to be trusted.

It is no credit to the industry to see the G-10 group come up with a suggestion that the European Commission could take initiatives to coordinate and publish data on morbidity and mortality across the European Union in different disease areas, similar to the role of the Centers for Disease Control and Prevention (CDC) in the United States. A key aspect of the role of CDC is that it is independent of the purchaser and provider healthcare framework. It is thus trusted by both patients and industry to provide impartial and accurate clinical data free from financial consideration, the group says.


Because the paperlike the G-10 itselfis a compromise, not everything in it is bad news for the industry as a whole or the clinical trials sector in particular. For instance, it suggests decreasing the bureaucratic burden imposed by the EUs new clinical trials directive, and avoiding undue delays in access to new therapies (in particular those resulting from biotechnology research) although without affecting the high standards for clinical trials, which are essential for the quality of research outcomes and market approval. 

The G-10 group urges the EU to support the development and marketing of pediatric forms and uses of medicines by developing incentives and other measures for pediatric research on new and existing medicines. Few will argue with its ideas on direct incentives to research (such as tax credits for research or tax allowances for investment), or on boosting access to venture capital by attracting private funds for new technologies. 

Most will welcome its explicit recognition that all new medicines introduced on the market are the result of lengthy, costly, and risky research and development conducted by the pharmaceutical industry. And its assertion that the financing of such R&D costs requires a sustained and substantial cash flow that the company is only able to generate if it launches new medicines on the various national markets as quickly as possible, at the best possible price. Everyone who has tried to launch a drug in Europe will be glad to see that the G-10 group admits that 

considerable delays are currently experienced in access to new, effective medicines in member states. These delays range from those occurring during the regulatory process itself, the issuing of product licenses after marketing authorization, in price negotiations and in reimbursement systems. There can be as much as four years between the first patient in the first member state having access to an innovative medicine and the first patient in the last member state enjoying the same access. 

The document is only a consultation paper at this stage. It will be modified before April 2002, and will only then be fed into the EU policy-making process. It needs modifyingif only to smooth out some of its uneven quality, which often amounts to contradiction rather than conciliation. But the pressures to modify it will come from all sides, including those interests that seek to subjugate the industry rather than liberate it. The clinical trials community may care to make sure it gets its own views across clearly lest they be ignored by default.            