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The pharmaceutical industry spends more than $156 million each year to support data transfer, and all involved parties could benefit from common interchange standards.

A Multidisciplinary Approach to Data Standards for Clinical Development--Progress Update

Process inefficiency and illogic is rampant throughout our industryin every sponsor, CRO, and investigative site. This new column will examine clinical trials operations from the process perspective. Its goal is to stimulate readers to recognize when, why, and how to improve the effectiveness of the way they do their work. The many quick and effective ways to improve this situation start with awareness.

Executive readers may protest that their company is well aware of the need for process re-engineering and that they have already spent millions to do it. Middle managers will groan at more talk about process improvement because they often have been the victims of their executives re-engineering projects. The frustration and lack of impact that result from these projects comes from the fact that too often, process re-engineering is only skin-deep.

Does this scenario sound familiar? A corporation decides to re-engineer its company to develop best-in-class practices. It spends millions on high-level interviews and executive brainstorming which, predictably, produce high-level goals like triple our pipeline in three years, or reduce our costs 10% every year for 10 years. Multicolored laminated diagrams elucidating the workings of interdepartmental teams are distributed company-wide and imprinted on coffee mugs. These goals become the objectives for middle managers to implement, the success of which will determine their bonuses. Meanwhile the executives congratulate themselves on having re-engineered the companythey have the wall posters to prove it. The rest is just details.Details indeed. How is a department supposed to respond to this dictum? Accelerating time-to-market is a key business strategy. With a re-engineering recommendation as specific as Regionalization of monitoring resources may be more productive, what is a manager to do?

The answer for clinical operations managers is to get the skills and tools needed to apply management action and group process to improvement tacticseither to attack inefficiency or to exploit a competitive advantage. The problem is, this is where the money runs out. Corporate leadership is often ready to spend millions on the skin cream, but has not been helped to understand the cost of the surgery needed underneath. Even when executives recognize that more detailed work is needed, they may find that their discretionary budget has run dry. So they turn to middle managersin time-honored traditionand say: Implement our Seven Points of Light, and do it while you get your regular work done.

Operations managers may have in fact been deeply involved in the re-engineering effort, at least in terms of time spent in interviews, team meetings, and exercises. But often they do not see the results of their input translated into a useful operational plan. In this way, managers feel the process improvement was done to them, not for them. The more frequently this happens, the greater the skepticism about process improvement that spreads among all staff.

This irony is repeated every year across our industry. The more it happens the worse it gets. Left unresolved, the inefficiencies create more financial pressure, which, in turn, demands more effort from clinical operations groups, who then have even less time to correct the problem. Clinical development is the longest, most costly part of bringing a new therapy to market. It deserves a sophisticated, deep approach to process improvement.

Although there is value in aligning a vast corporate enterprise around a set of clearly defined business strategiesespecially for the sprawling merged entities we have in our industry, and the CROs that have grown far beyond managing by instinctit is also essential to develop specific tactics for implementing those strategies. Once strategies are in place, those who suggest they are bringing value to the corporation through process improvement must be willing to get their shoes muddy, and they need to have the skills to lead the operations group through that mud.

Clinical operations managers need to anticipate this impact of skin-deep re-engineering and arm themselves with skills and resources to respond, while trying to influence the situation proactively. Here are some suggestions. Future columns will discuss these and other techniques in more detail.

	Routinely propose budget dollars and resources for process improvement in your annual plansand defend them vigorously.

	Raise the consciousness of your bossesand their bossesabout the importance of tactics.

	Learn tactical improvement techniques, such as fact-based interviewing and process mapping.

	Watch out for reorganization plans based on politics instead of process. 

Organization charts are the language of a corporate personathey are too important to be determined by whose job needs to be protected or how to support a managers compensation through head count.

	Protect yourself withand learn frommetrics. Measure the way you work now so you can see how the imposed changes affect you, for good or ill.

	Dont try to save a bad process with technology before you understand the process problems.

Clinical development is in crisis. Superficial re-engineering does not help. It is in your hands to make your organizations inner beauty shine through. Beauty may be only skin-deep, but process improvement need not be.            

Process Improvement

Many re-engineering projects neglect the nuts and bolts that are needed to make strategies a reality.

When Process Improvement is Skin-Deep

The information age defines todays workplace, now populated with a plethora of handy communication widgets, from pagers to cell phones to PDAs. Project managers are at the forefront of directing communication flow through these various channels. In an R&D environment, effective communication is critical. Project managers build a team and establish their leadership through clear, concise direction. Yet, at some point in a project life cycle, a walk through almost any team meeting yields snippets of conversations that reveal, Weve got a communication breakdown.

Despite all of our electronic aids, or perhaps because of them, communicating effectively does not come naturally to many people. The basic skills of speaking, reading, and writing are taught very early in life, and we may incorrectly assume that once those are learned, that is all it takes. However, good communication is based on a fundamental understanding of human behavior. A savvy project manager is an astute student of psychology and a trained facilitator. If project managers understand how people act and react, what habits they have, and what motivates them, it is relatively easy to decide how, when, and what to communicate effectively to get the desired result.

The basic work unit in pharmaceutical R&D is the project team. Whether it is openly stated or not, the most important core competency of the project team is communication skills. Teams that perform poorly often cite communication breakdowns as a root cause of their problems. Teams that perform well, on the other hand, have a number of success factors, but among the most important is a project manager with highly developed communication skills and the ability to foster communication throughout the team.

Most project managers are responsible for interacting with two groups: their project team and senior management. Many project managers also interact closely with their clients. Each group has different needs, expectations, and motivations. Communication techniques should be selected to meet the special needs and requirements of each group as well as individuals within these groups. 

Project managers have a special responsibility to disseminate the information they receive, because they sit at the hub of a communications network. Information about the project is channeled to them from many sources, including information only indirectly related to their project. No one on the team has more information than the project manager, and people assume the project manager is routing that information. Consequently, this is often the first place where communication breaks down.

Project managers must strike an appropriate balance between providing too little and too much information. Each group should receive the information required to do its job. The same should hold true for each person within the group. People need to be properly informed and included in discussions of issues affecting them; nobody likes to be left out. On the other hand, being flooded with unimportant or irrelevant information is distracting and annoying. It takes valuable time to sift through mass communications. Wading through irrelevant items can cause one to overlook something really important. The checklist outlines common criteria for making communication more effective. If enough time and consideration are taken to issue appropriate communications about a project in a responsible manner, the project team, management, and client will not only be grateful, but also more effective in their jobs.  

However, even when the criteria in the checklist are followed, communication may still be ineffective. On my first trip to Germany, bone-tired from a long flight, I switched on the hotel room TV to find a rerun of Lassie, dubbed in German. The story reached that climactic moment when little Timmy turns to Lassie and tells her to go for help. My immediate reaction was You crazy kid, that dog doesnt understand German! But dogs dont understand English, either. 

There is an important lesson here: The spoken word is only a small component of communication. Timmy could speak any language at all to Lassie. She understood her master by noting his vocal tone, visual cues, the context of the situation, and consistent past behaviors. Similarly, visual cues, vocal inflections, context, and past experiences play a big role in the way we communicate with other humans. Words are important only as a framework for the other factors in determining what the recipient concludes from our communication. When communication fails, it is because the behaviors, habits, and personalities of the two parties place different interpretations on what the words mean. 

Effective communication requires the participation and cooperation of two parties: senders and receivers. Project managers play a key role by setting a good example and facilitating the flow of information between other senders and receivers. Most breakdowns in communication are the result of misunderstandings between senders and receivers. The Behavioral Barriers box lists examples of typical communication breakdowns.

Technological innovations have introduced many new communication tools (email, voice mail, faxes, cell phones, Internet chat rooms). One might think that todays communication must surely be better than in the days when we sealed envelopes with wax and had them delivered by a messenger on horseback. Not so. New technologies simply make it easier to send words. Methods for ensuring accurate interpretation and appropriate actions by the recipients of those words have not advanced. Such comments as I cant read your mind and I didnt get the message are clues that human behavior is a contributing factor. Techniques to overcome that kind of communication breakdown require more from human psychology than from technology.


Poor communicators often share the misconception that somehow everybody knows exactly what a speaker means (whether it is actually said or not), and automatically acts the way the speaker expects without additional prompting. If they dont, its labeled as a communication breakdown. The sender wonders why they dont get it. Often, the sender fails to take into account the recipients personality, habits, and focusand therefore misjudges the way the recipient will interpret and react to the message. To correct this, first ensure the right message is being sent by meeting the criteria listed in the checklist (see below)

Information that is transmitted clearly, accurately, professionally, and in a timely manner facilitates a teams work, managements understanding of project progress, and the clients confidence. More importantly, though, project managers should be attentive to the behavioral barriers to communication. Misunderstanding, mistrust, and inefficiency can result when a message is transmitted in a way that makes it difficult for the team, its management, and the client to easily and appropriately act upon the information. 

The needs of those groups may differ and require customization. If a project loses a key contributor, for example, the remaining team members may need to know how much extra work will be expected of them. Management, however, may need to know about the likelihood of higher operating costs, and the client may want to be reassured that the original timelines and deliverables will still be met.

Communication breakdowns may be compounded when an action is expected from the recipient. In this situation, the recipient must go beyond understanding the senders message. For successful completion, the recipient must accurately interpret what is expected of him or her and be motivated to actually do it. 

Project managers must often lead teams without the benefit of a reporting relationship. Even when they do, they cannot always rely on team members to act upon every request simply because it was given. Recipients may readily agree to act, but fail to follow through for any one of a number of reasonsthey may be busy, they may forget, they may have a higher priority task. In some cases, a team members supervisor simply overrules a request from a project manager. 


The hurdles to understanding and motivation may be avoided by applying the simple Rule of Three. Make a request three times in three different ways. Its easy to forget a request when it comes from someone who doesnt write your performance appraisal. Its hard to avoid it when asked a second time and given a chance to clarify any ambiguities, including the scope of work and completion date. By discussing the request a third time, the recipient risks being labeled rude or incompetent if the request is still ignored. 

Misunderstanding goes both ways. The Rule of Three provides an opportunity for feedback on the way a request was actually received. It offers an opportunity for the sender to clarify ambiguities and may identify competing priorities the recipient must manage. The feedback may also provide insight as to why a recipient is reluctant or resistant to a request. Finally, thorough follow-up may reveal that the original request was more complicated or difficult to complete than intended. This feedback provides an opportunity to redefine or reconsider the original request, and provides information about ways to motivate a recipient more effectively.

Using multiple communication channels enhances the probability of reaching the recipient. Rather than leaving repeated email messages, try the telephone or a fax. Contact a colleague to determine whether the intended recipient is on vacation or otherwise out of reach. Make sure that follow-up messages are consistent, even-tempered, and to the point. Avoid the temptation to use sharper and more critical language, as this can increase the potential for conflict. The tenth message should be as calm and professional as the first. Inflammatory language only makes it more difficult to get the necessary cooperation to complete the task. 

The Rule of Three is an effective communication method. It reduces the impression that recipients must be able to read minds. Its application creates an environment and forum for resolving misunderstandings before they become issues. At the same time, it offers greater incentives by identifying useful motivational factors and helping to ensure that requests are acted upon. 

 Some communication failures come from people who complain that they are deprived of information to which they feel entitled. It is the project managers responsibility to ensure that team members have all the information they need to do their jobs. In addition, the team will work more effectively together if they have a general understanding of what their teammates are doing and get regular updates on overall project status. Status updates are also critical for senior management and clients, who need to make informed decisions affecting the project.

Tailor a message to its intended audience.

 Team members need specific details to plan their work and coordinate hand-offs among teammates. Senior managers and clients may not wish to know every project detail as long as they are clearly and regularly apprised of the projects progress, budget adherence, timetables, and quality of workmanship. If any factor is not meeting management or client expectations, the project manager should take the initiative to provide more detail along with proposed solutions.

 Some people use the tactic of not getting the message as a way of saving face. It is a graceful excuse for people who fail to meet a deadline, forget an action item, or come to a meeting unprepared. If there is a pattern in which one person fails to get messages more often than others, the mail system may not be the problem. It is unlikely that messages fail to get through when the Rule of Three is consistently applied. Team leaders cannot force people to read, listen, or respond, but they can anticipate and compensate. Dont assume that they are getting the message. Despite technical breakdowns, piles of incoming mail stacked on a recipients desk, and unexpected absences from the office, make it impossible for recipients to claim they never got the message or never saw it. Follow up. Remind. Confirm.


When people complain about communication breakdowns, they generally imply that it is the other guys fault: They are failing to communicate properly with me; Im not the problem. If only somebody would fix the other guy, everything would be okay. If communication is ever to improve, however, each team member must assume personal responsibility for fixing it. Others can be influenced but not controlled. 

Modern communication tools improve the ease of sending information, but they do nothing to improve listening and understanding on the receiving end. Recipients are not required to read incoming messages, and there is no way to adequately determine whether or not they do. Furthermore, although they may be extremely convenient, some electronic tools (such as email, voice mail, and faxes) are much less interactive than face-to-face communication. Unless they talk directly, senders cannot be certain when or how a message is received (if at all), whether a message is understood, or when and if a recipient will act on a message appropriately. Understanding the limitations of communications devices and how people use themor dont use themis a key to successful communication. And using the Rule of Three can help to ensure that messages are reaching team members in the way they are most likely to receive them. 

Encourage team members to follow up with one another and, when appropriate, with the client. Communicate in ways that take peoples feelings and motivations into account. Dont become a victim of technologys limitations. Project managers cannot control other peoples behavior, but with a little psychological insight and follow-up, they can anticipate, compensate, and minimize the negative impact of their communications.


Despite their convenience, modern communication technologies have improved only the speed of transmitting words. Over 90% of communication is achieved through body language and vocal inflections. Less than 10% actually relies on the words that are used.

Near real-time electronic communication provides ample opportunity to act on misunderstanding rapidly. Consider the impact of faster word transmission. A sender may innocently transmit information that a recipient takes out of context or misunderstandsand interprets negatively. Electronic communication tools accelerate and amplify the negative spin. Time is lost while the sender and recipient, and perhaps others, struggle to undo the misunderstandings, pursue meaningless issues unrelated to the original intent, and soothe hurt feelings.

Modern technologies have redefined the speed with which business is done and are both a blessing and a curse for project managers. Cycle times, customer service expectations, and many other business practices all presuppose that workers can respond quicklyoften in real time. Traditional postal delivery is now called snail mail and e-business is the norm. This can encourage team members to act before they think, before they check all the facts adequately, and even before they have complete input from a sender.

Electronic communication is attractive to many people because it is convenient, fast, and fun to use. However, a comparison of the time it takes to formulate a thoughtful and appropriate response with the time it takes to sort out the repercussions from hasty action reveals that greater efficiency often results when communication proceeds more slowly and deliberately. Certainly, when high-tech communications are used effectively, they can enhance customer satisfaction and reduce cycle timebut only as one component in a repertoire of communication choices.

Another reason modern communication technologies are attractive is that they are impersonal. All sorts of messages can be sent, including bad news and inflammatory remarks, without seeing the recipients reaction. It is human nature to avoid conflict, which is unpleasant and may be threatening. Conflict also implies fighting until one party winsand no one wants to lose. Email provides a particularly attractive forum for fighting battles. By defending a sensitive issue through email, a sender can avoidor at least have an illusion of avoidinga potentially embarrassing situation. Winning the respect of highly regarded colleagues takes time, and one awkward performance in their presence can damage that hard-won respect. Through email, the opponent doesnt have to be faced, and the battle can be waged on the senders own scheduleaway from the probing eyes of influential people. 

Project managers are often challenged to do all they can to keep team communications constructive, effective, and aligned with the ultimate goals and objectives of the project, and a phone phobia may stand in the way. Whether it is caused by attraction to high-tech toys, avoidance of conflict, or both, project managers and team members may be prone to such phobic behavioran inability to simply pick up the phone and speak directly with the other party. Even better than picking up the telephone is a walk down the hall to talk face-to-face. Direct talk on the phone or in person is often resisted because it is both low-tech and emotionally stressful. It is, however, by far the best choice when dealing with bad news or difficult issues. 

Talented project managers avoid impersonal methods when communicating bad newsa time when emotions run high, issues can be difficult and complex, and time is typically constrained. Sensitive situations often require problem-solving sessions and are best done in a setting that fosters discussion. Avoid propagating volleys of increasingly inflammatory email. It builds walls. Small problems can be elevated to monumental heights, evolve into other topics completely off the original subject, and generate hurt feelings on both sidesall of which are unnecessary. Face-to-face interaction builds bridges. Parties have a better chance of connecting because they can use visual cues and visual aids, discuss things interactively, and work out the problem together. 

It is important to remember that people rarely set out to be nasty. But when a recipient perceives a message as hurtful, the perception may linger and a relationship may be damaged. Even among close colleagues, a poor choice of words can contribute to misunderstanding. The chance of miscommunication is compounded when communication involves different languages and cultures. A project manager must balance the need for speed against the need for accuracy and completeness. Encourage and foster opportunities for direct talk.

Speaking, reading, and writing are among the earliest skills learned in life. By the time people are adults, the way they use these skills is so instinctive and ingrained that they give little conscious thought to the way they use them. Speaking is not the same as communicating. What someone reads is not always interpreted in the way that the author intended. In drug development, project managers are at the center of directing these interactions and must always be mindful that communication can fail if they fail to recognize the importance of context, experience, emotional state, and visual cues.Although email is faster than a quill pen and cell phones are more fun than Morse code, modern technologies do not ensure better communicationonly faster transmission of words. Senders need take the initiative to ensure that the messages they transmit can be understood as intended, particularly in our increasingly global work environment.


1. You Dont Say! Communication Skills (Crossroads Group, 247 North Bent Road, Wyncote, PA 19095, 1993).


Joan Knutson, You Owe Your Project Players a Communication Infrastructure, Part 1, PM Network, November 1999, 2122.

Joan Knutson, You Owe Your Project Players a Communication Infrastructure, Part 2, PM Network, December 1999, 2324.

Michael Kemp, Learning to Listen, PM Network, February 2001, 5962.Thomas J. Purcell, Enhancing Electronic Communications between Team Members by Establishing Best Practices: A Communications Specialists Perspective, Drug Information Journal, 35, 3540 (2001).

Carol L. Grimes, Communicate, Communicate, Communicate, PM Network, May 2001, 20. 

Carlo Donati, Communication Skills for Monitors, Applied Clinical Trials, July 2001, 3639.

SIDEBAR: Behavioral Barriers to Communication


Some typical examples of communication breakdown:

	Senders writing style may be offensive (too friendly, too stiff).

	Senders mood and emotions may creep into the writing style.

	Sender says one thing but means something else. 

	Sender overestimates what the recipient knows.

	Sender makes different assumptions than recipient.

	Inaccurate information is purposely communicated.

	Action required by receiver may be unclear.

	Receivers interpretation may differ from the senders.

	Receiver may avoid or delay a required action.

SIDEBAR: Checklist for Effective Communication

	Communicate information in a timely manner, neither too late nor prematurely.

	State the purpose of the message clearly.

	Include sufficient information in the message.

	Give specific information, neither too detailed nor too general.

	Avoid information overload, eliminate everything that is irrelevant.

	Make information clear and concisewell-written and of sufficient depth.

	Use familiar jargonwords and phrases understood in the work group.

	Use an appropriate formatfor example, tables vs. graphs.

PhD, is a drug development consultant with Covance Inc., 1452 Quail View Circle, Walnut Creek, CA 94596, (925) 930-2840, fax (925) 930-2860, email: rebecca.anderson@covance.com.

Technology can do only so much; understanding human behavior and psychology is the key to improving your communication skills.

Communicating in the Information Age: It?s Still All About Human Behavior

A major thrust of the Bush administrations budget plan for 2003 is to shore up the nations defenses against terrorism. The result is more funding for biomedical research by the National Institutes of Health and for efforts to spur development and approval of new drugs and vaccines by the Food and Drug Administration. The focus on combating bioterrorists, though, has removed efforts to protect participants in clinical research from the limelight. The buildup in human subject research protection efforts that began last year will continue, but there are few added resources in this area. 

The budget plan for the Department of Health and Human Services (HHS) gives a slight boost to the Office of Human Research Protections (OHRP). It will gain $1 million, for a total of $8 million, to implement HHS rules, negotiate formal assurances with research organizations, investigate compliance issues, and support professional and public educational efforts. One new initiative is to strengthen ties with international organizations involved with human research issues. 

Even though HHS proposes a $1.7 billion FDA budget for 2003, up $123 million, it includes no additional funding for clinical trial oversight. Last year, FDAs budget proposal listed protecting volunteers and the integrity of data in clinical trials as a top priority. It boosted FDAs resources by $10 million to increase clinical trial inspections and to better coordinate bioresearch monitoring (BIMO) activities for drugs, biologics, and medical devices. For 2003, the administration aims only to maintain the higher BIMO inspection levels gained last year. Expect this to involve about 750 site visits concerning drug research, 190 inspections concerning biologics, and 270 inspections concerning medical devices. There will be 100 foreign BIMO inspections for drugs and a handful for biologics and medical devices. 

Efforts to bolster protections for participants in high-risk clinical trials such as gene therapy studies remain a priority for FDAs Center for Biologics Evaluation and Research (CBER). The center will provide more guidance in this area and is developing a gene therapy subject tracking system to assess and promote the safety of individuals participating in these high-risk studies. FDAs Gene Therapy Monitoring Analysis Working Group will review clinical monitoring programs, identify common variables of inadequate programs, evaluate the quality of gene studies, and identify sponsors or investigators with financial or other significant conflicts of interest. CBER plans to convene a conference of investigators to discuss monitoring practices further. 


FDAs budget plan provides about $450 million for the Center for Drug Evaluation and Research (CDER) and $200 million for CBER to support timely approval of new drug applications. Other key budget features include:

 ($29 million). Prior to this year (2002), the agency had to cover the mandated cost-of-living adjustments and raises out of its general appropriation, which translated into an actual reduction in resources available for program operations. 

 to permit more timely inspections of regulated products. A major thrust is to increase inspections of domestic food processors and food imports, but the agency will gain about $10 million to conduct more inspections of U.S. and foreign manufacturers of drugs and medical products, and to maintain current levels of BIMO inspections, as noted above. 

 initiatives and programs to reduce adverse events related to drugs and medical products. FDA will gain $5 million to improve its adverse event monitoring system and to support FDA involvement in government-wide patient safety initiatives. These funds will support electronic data entry initiatives to enhance FDAs adverse event reporting system (AERS) and to encourage more reporting by drug manufacturers. 


Much of FDAs added resources come from $160 million provided to counter possible biologic-based terrorist attacks. This amount includes $54 million to encourage the development and production of new vaccines, drugs, and diagnostic tests that could be used to protect the public health in emergencies. Many activities fall under this heading, including research on novel methods for evaluating new drugs and diagnostics to ensure safety and effectiveness. 

One important initiative is to finalize a proposed rule for testing therapeutics to treat lethal diseases. The policy would apply to situations where controlled efficacy studies in humans cannot be conducted due to ethical and safety concerns. A final rule is in the works to identify what information is sufficient to provide substantial evidence of efficacy in new drugs and biological products likely to reduce or prevent the toxicity of chemical, biological, radiological, or nuclear substances. 

Another goal is to develop procedures and protocols to permit the use of investigational therapies in emergency situations. 

Andrea Meyerhoff oversees these efforts as director of antiterrorism programs in the office of the FDA commissioner. She serves as FDAs point of contact on bioterrorism for other government agencies, as well as for FDA centers. One of her tasks is to identify medical products in the development pipeline that might address bioterrorism concerns and be needed in a health emergency. Meyerhoff offers assistance to companies unfamiliar with FDA policies that are developing new therapies or diagnostic technologies with public health benefits. 


All these funding increases for FDA assume that Congress will approve a huge increase in user fees collected from manufacturers under the Prescription Drug User Fee Act (PDUFA). The budget calls for a whopping 60% jump in fees for biologics and drugs to almost $300 million, up $103 million over this years total. One result of such an increase is that user fee revenues would underwrite more than 50% of FDAs new drug review program, exceeding the original limit set by Congress. In fact, without such a big increase in fee revenues, the total FDA budget would rise by only 1.3%.

FDA insists that it needs more money to balance the current mismatch of workload and revenues, according to acting senior associate commissioner for management and systems Jeff Weber. The agency also wants to boost user fee revenues to support risk management initiatives and other postmarketing safety efforts mentioned above. Unfortunately, FDA has seen a big drop in fee revenues in recent years because sponsors have filed fewer applications with the agency and are seeking more waivers than anticipated. 

Negotiations for PDUFA 3 are going on, and there is grumbling about the proposed fee hike from manufacturers, particularly smaller biotech firms. FDA envisions funding postapproval initiatives with a hike in product fees, as well as higher application fees. Some relief may come from recently approved legislation to renew the pediatric drug labeling program, which authorizes application fees for pediatric supplements. Moreover, FDA is talking to generics makers and medical device companies about paying fees for application reviews. PDUFA 2 expires Sept. 30, which means that FDA and industry need to reach some agreement this spring. Unlike previous years, the agency has used all of its user fee reserves and will have to lay off staffers if the fee program is not reauthorized well before its expiration date. 


With the Bush administration heavily promoting biomedical research to combat bioterrorists, theres little surprise that the National Institutes of Health are slated for another big funding boost. The budget plan seeks to increase total NIH funding by almost $4 billion to $27.3 billion, fulfilling promises to double the agencys budget in five years. Cancer research gets a big boost, as does R&D related to AIDS. 

The NIH total includes $1.75 billion to counter bioterrorism, which NIH will use to spur new product development. The agency will invest about $440 million in basic research, according to Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID). Another $500 million will support construction and improvement of research facilities. More unusual is the agencys plan to invest considerable resources in R&D likely to lead to development of specific diagnostics, vaccines, and therapies. NIH will be looking to arrange more partnerships with manufacturers and researchers through links with research institutions and through innovative licensing agreements.

At the same time, the HHS Agency for Healthcare Research and Quality (AHRQ) faces a sharp budget cut of $50 million, to $251 million. While funding continues for several subject safety initiatives, AHRQ will have much less money to fund outside researchers studying health outcomes, quality, and costs. The proposal threatens AHRQs Centers for Education and Research on Therapeutics (CERTs), which conduct research on efforts to improve the safe and effective use of medications. 

Now Congress will take its usual swipe at the administrations spending plan. AIDS activists are protesting cuts in HIV prevention programs, while AHRQ supporters are lobbying for a 30% increase in that agencys budget. Some policymakers are complaining that the continued boost in NIH funding deprives other agencies of a fair share of federal research dollars; double-digit increases in the NIH budget may be a thing of the past. 

SIDEBAR: Medicare May Cut Support for Cancer Trials Subjects


Cancer patient advocacy groups are up in arms over signs that the Bush administration seeks to change the current Medicare policy of paying the routine costs of care for subjects participating in certain qualifying cancer studies. The Clinton administration approved such coverage two years ago (July 2000) to encourage more elderly patients to participate in cancer studies, as well as to provide equal access to experimental treatments for Medicare beneficiaries. The American Cancer Society and a long list of patient advocacy and cancer organizations are protesting any rollback. A prime concern is that the Medicare coverage policy would affect decisions by health plans and private insurers about supporting subjects participating in clinical trials.

SIDEBAR: FDA Gets New Deputy Commissioner


After months of stalemate between the White House and Senate Democrats over the appointment of a new commissioner for the Food and Drug Administration, Health and Human Services secretary Tommy Thompson took a short cut and named a new deputy commissioner to head the agency temporarily. The new deputy, Lester Crawford, was able to start work immediately after his 26 February appointment without going through a lengthy Senate confirmation process.

Crawford was considered a top candidate for the commissioners job last fall. As a food safety expert and veterinarian (DVM), he appealed to Thompson as someone able to promote FDAs role in ensuring the quality and security of the nations food supply. Crawford most recently headed Virginia Techs Center for Food and Nutrition Policy and served in the Department of Agriculture and as director of FDAs Center for Veterinary Medicine in the 1980s. However, consumer advocates objected to his appointment due to strong ties to industry; Crawford also has held positions at the National Food Processors Association and at an agricultural chemical firm. Moreover, Crawford is not an MD, a usual credential for the FDA commissioner.

With Crawford coming on board at FDA, Bern Schwetz is able to return to his job as the agencys senior advisor for science after being FDAs acting principal deputy commissioner for more than a year. Thompson and the White House insist that they are actively looking for a new permanent FDA commissioner, but this appointment gives Crawford an opportunity to audition for the job. The Bush administration recently rejected Alastair Wood of Vanderbilt University as a possible commissioner, apparently due to strong objections from pharmaceutical companies. Senate Democrats have nixed anyone who appears too pro-industry. If the impasse continues, Crawford could remain the de facto head of FDA for some time.            

View from Washington

Human research protection takes a back seat, as the White House boosts funding for NIH and FDA?along with FDA user fees.

Terrorists Steal Limelight from Human Subjects

Ctrl-alt-del. Nothing. I am beyond the frozen computer, beyond the blue screen of death, looking at the rarely seen BIOS message with the little bird. Most of you have probably never seen this, but I have, on several occasions. Why? Anyone in my IT department at work will tell you that I am promiscuous with my computer. I love to download software, especially if it is free, or nearly free. I am a shareware and freeware addict. 

You can be sure that I have my reasons, and they are good ones. First of all, I have a bunch of hobbies that have generated many shareware and freeware computer programs. There are amazing software programs for amateur astronomerscomputer planetariums, artificial satellite locators, and observation databases to name a few. Similarly, contract bridge and rock-climbing enthusiasts have developed many software programs that are distributed freely on the Internet. Even my serious professional interests, such as medicine, are the subjects of hundreds of very useful shareware computer programs.


Shareware and freeware programs often answer my needs. And they do it quickly. For example, I might be cataloguing my CD collection in Microsoft Excel when I begin to wonder whether anyone has developed a shareware program for this purpose. A quick search through Tucows Downloads (www.tucows.com) or another similar shareware/freeware repository may net a dozen or so potential files. I may download a few and try them before settling on the one that works best. Along the way, I install and uninstall the losing entrants. Some of them may crash my computer or fail to work. Many have no support or information other than a very skimpy help file that comes with the program. Worst of all, most leave traces in the form of .dll files and other installed files on my system. These little time bombs are waiting for just the right moment (usually when I am busy writing an article on deadline) to unleash their particular damage. The result is a flaky computer with frozen or slow screens, the blue screen of death, or worse.

Shareware and freeware give users like me a quick fix. Often, I will use a shareware program for a few days, then gradually lose interest in the particular application that I am using the shareware for. If the program is free, I have lost nothing (or so I think!). If it is shareware, often I have not had to pay the modest fee for the program until I have used it for more than 30 days. Usually by then I have figured out whether I want to keep the software and pay the registration fee. 

The problem is that freeware and shareware programs are designed and developed, for the most part, by individual and amateur computer programmers who are earnestly interested in providing software for people who share the same interest. Although talented professional programmers produce some shareware, individual programmers, who have little experience in the production and distribution of computer programs, produce much of it. They may not use the best tools for programming or may be unable to do adequate quality control and testing of the software, and costs may prohibit the testing of the software in all of the possible environments (different versions of operating systems, different computers, simultaneously running software programs). The result is that many freeware and shareware programs are fragile, operating improperly under some circumstances. Much more problematic, these programs can interfere with existing software and the operating system itself, causing erratic behavior and crashes. The time and effort required to fix these issues can be enormous, far outweighing the savings of using a shareware program.

Would I have had the same issues if I had used an off-the-shelf, shrink-wrap, program? Shrink-wrapped software is retail softwaresold on the shelf in stores like Staples, easily installed by the purchaser, and frequently boxed and wrapped along with the license. There is little relationship between the company that developed the software and the purchaser. Shrink-wrapped software is common in markets with enormous numbers of users; for example, word processing or spreadsheet software. I would probably not have had the same problems with off-the-shelf software, but there are no guarantees. Typically, commercial software, especially from reliable and well-known software companies, has been developed using modern techniques and software design practices, and it has been tested properly to ensure that it functions properly in many settings. This disciplined software development and testing is expensive, which is part of the reason that high quality software typically costs far more than shareware. Although the marginal cost of cutting a CD with software on it is pennies, the development and testing process for quality software can range from millions to tens of millions of dollars.

 Interestingly, there are several freeware programs that can be used in clinical trial applications, typically in pharmacology, pharmacokinetics, and power/sample size estimation. Typically developed by an academic statistician or pharmacologist, many of these programs are DOS based. Although they may not be beautiful to look at, these programs may work as well as their expensive commercial cousins that do more or less the same thing.

Issues concerning freeware and shareware software programs may seem fairly distant from the clinical trial software that is being developed for pharmaceutical companies. In fact, some of the same considerations already discussed play a role in choosing software for a clinical trial application.


Clinical trials software is not typically the shrink-wrapped software that most people are familiar with. Most clinical trials software is either custom developed or sold as commercial enterprise software. Custom developed software is purpose-built. It can be developed by a pharmaceutical or a biotechnology company based on detailed specifications, or by consulting software companies. Custom-built software can be extensively tested in the exact environment in which it will be used. The builders of the software may be able to build the software to work in a particular networks architecture, on particular computer systems, because this type of software can be specified and standardized. Custom-built software can be carefully specified to work exactly as desired. It is like a Saville Row custom suit. The custom nature of this software can also be its downfall. Most major software needs bug fixing, updating, and linking to other software programs. With custom software, these activities must be done by software programmers. Thus, the ongoing support of such custom programs requires continued cost and effort from the developers. Of course, the developers also must properly validate each version of the software for use in clinical trials.

Commercial enterprise software is an alternative to custom-built software that provides a robust solution, but may require more process reengineering than custom-built software. The installation and configuration of such software can take a considerable amount of time, as can the training of support staff and end users. Of necessity, commercial enterprise software is developed for a common denominator of users, and therefore may be a less perfect fit for each user than is custom-built software. 

This type of software solution typically costs far more than shrink-wrapped software for several reasons. The software typically has a much more limited market than shrink-wrapped software. The cost of developing and testing the software is therefore spread over far fewer purchasers. Finally, commercial enterprise software is often highly complex, requiring many dozens of developers to write, test, and document the software. This type of software serves as a stark contrast to freeware/shareware.

Commercial enterprise software provides a number of advantages for the licensee. Typically this software is extensively tested to work in many different settings. In addition, the commercial vendor is typically committed to the continued development of new versions of the software, product extensions, and links to other related software products. Third-party vendors may develop add-on products that meet particular needs of the user and are far less costly than developing the same add-on as a custom product. As with custom software, each new version requires validation for use in clinical trials. This validation effort can be partially performed by the vendor for all users of the software.

A final consideration is that of open source software. Typically, commercial vendors of software license an executable version of the software. The underlying computer code that was used to develop the software cannot be viewed or modified. If the actual computer source code is available to the end user, this is known as open source. Open source software is very popular in the academic world where many open source applications have been developed, especially for the UNIX computer system. In theory, developers can modify the source code and improve the software. Through the work of many expert developers, and with a central mechanism to merge the updated source code, the open source software program can be developed through many versions of improved functionality. Each version is tested by the user community, and bugs are fixed by volunteers. Many excellent computer programs have been developed this way. In fact, the LINUX operating system, a popular alternative to Windows, was originally developed this way and later commercialized.

Commercial vendors can also offer open source software simply by providing the source code along with the software. When this is done, the individual licensees can use the source code to modify the software. The result is that each purchaser of the software will be able to quickly develop a semi-custom version that requires full validation prior to use. In addition, once the licensee modifies the source code it becomes virtually impossible for the vendor to develop new versions or modifications of the original software. These changes or additions will no longer work with the original software. Thus, the licensee must commit to supporting, developing, and validating their personalized version of the software for its usable life. Commercial open source software cannot be supported by a vendor that cant possibly understand how it has been changed.


The development of software is a highly complex process that requires proper requirements, specifications, design, implementation, and testing. Failure in any of these arenas can lead to problems that can vary from system instability to data loss. The user of any software must be assured of the quality and stability of the system they are using or take big risks. With personal software, there are generally fewer risks with name brand, popular software products that are in broad use. With enterprise software, these same considerations are more difficult to make. Custom-built software must have a built-in process and a software development life cycle that guarantees the robust operation of the software. Anything less has far more consequences than merely damaging a personal computerit can interfere with data integrity and productivity. Commercial enterprise software must also be evaluated and validated along with the software vendor. The expectation is that future modifications and versions will follow a similar process. Finally, open source software is somewhat of a hybrid between custom and commercialit requires careful evaluation and validation, but once modified it becomes the responsibility of the purchaser to assure the continued integrity of the system. With all software for enterprise use, think about the total cost of software ownership. Caveat emptor!            

Technology Viewpoint

Take a tour through the world of freeware, shareware, shrink-wrapped, enterprise, and open source software.

A Rose by Any Other Name

You need more than the normal number of fingers to be able to count on one hand the number of changes in the air for Europe, its pharmaceutical industry, and the clinical trials sector. The European Union is on the brink of major political and constitutional changes that will affect everything from democratic rights to drug research. The EU is also laboring its waynot without difficultythrough a major rewrite of its specific legislation on pharmaceuticals, touching everything from data protection to adverse reaction reporting, and from registration procedures to regulatory competition. Now the clinical trials sector is between a rock and a hard place, trying to plan upcoming trials without knowing precisely how the new clinical trials directive will be implemented across key issues ranging from informed consent to the role of investigators.


At the macro-political level, the EU is being pushed by twin challenges into a profound review of its future. The most obvious pressure is the impending expansion of the EU into Eastern Europe and the Mediterranean, which will increase its membership from the current 15 countries to nearly 30, and which demands a streamlining of the EUs cumbersome decision-making procedures. To perceive just how big a challenge this is, you need only to reflect on how slow and tangled the discussions on changes to Europes pharmaceutical legislation are at present, and then to extrapolate that complexity into a Europe with nearly twice as many competing voices when EU ministers come together to make decisions. The average time for an EU legislative proposal to be adopted and come into force over recent years has been around three years. There is every risk that, without some speeding up of the process, a larger EU could take six rather than three years to agree on a rule such as the new clinical trials directive.

Equally important, however, is the more complex debate about what this larger Europe will be, what its fundamental aims should be, and how its different institutionsthe Parliament, the Commission, the Council of Ministers, and so onshould interact. This is largely driven by a growing recognition that, among most of its 300 million citizens, the EU is not a popular organization. It is seen as bureaucratic and remote, and even as irrelevantas is demonstrated by the plummeting voter turnout in the periodic polls for the European Parliament (around 30% of the population at the last election), or the recent rejections by popular referendum of the Euro in Denmark and of the new EU Treaty in Ireland.

So, in a bid to engage Europes citizens in fixing its objectives, a yearlong debate on Europes future has just got underway. Among recent contributions to this diffuse debate, one of the observations most relevant for the pharmaceutical sector came in early March from the leading French socialist Martine Aubry (the daughter of Jacques Delors, the European Commissions most effective president ever, whose energetic term of office spanning the 1980s and 1990s is remembered with affection by most Euro-enthusiastsbut a redoubtable figure in her own right). She told a special conference of the European Socialist Party, convened specifically to debate the partys position on the debate on Europes future, that the EU should aim to promote European research, so that Europe will not fall victim to the monopoly of U.S. drug multinationals.


There will be plenty more of that over the coming year, as the EU prepares itself for a new rewriting of its basic Treaty and a new definition of its destiny.

But closer to home, the coming year will also see the debate open up on the EUs attempt to rewrite its drug rulesa rewrite ostensibly aimed at speeding new medicines to patients. Already the European Commissions proposals have run into heavy opposition from the drug industry and from some of the biggest EU member states. Topping the list of problems is a plan to limit industry choice on how drug companies put their drugs on the market. The Commissions proposals envisage obliging drug firms to submit every application for authorization for a new product through the EUs so-called centralized procedure, operated by the European Medicines Agency in London. This would eliminate the current choice open to firms to use the alternative national authorization channels first, and then to enter the market in other member states on the basis of the mutual recognition procedure. It would also cramp the style of leading national drug agencies. The UK and the northern European countries have already started to openly criticize the plan.

Industry is also anxious about proposed new requirements for compulsory product launch within three years, on pain of losing the authorization. It objects to the limitation to a single trademark for new products. It is apprehensive over possibilities that differences in member states assessments of products already on the market under national authorization procedures might automatically lead to an EU-level arbitration procedureand the risk of a product suffering changes to (or even losing) its authorization in one member state because of objections in another member state.


But at present, the drug industry in Europe is most concerned about the way the new EU clinical trials directive will operate. The directive, adopted in 2001, is due to come into force at the national level across the 15 member states in May 2004. But before then all the details of its implementation have to be defined via guidance from the European Commission. Since November 2001, member state experts have been discussing a series of drafts from the Commission, but the earliest date for this consultation to be widened to the industry is currently June 2002implying still further delay before it is finalized and published. Industry has already repeatedly complained that it is being excluded from the process, and is now fearful that the guidance may not only be inappropriate, but may also come too late.

Some of the key areas for which the guidance is needed include:

 The issues include the content and format of companies applications to ethics committees to run a clinical trialand discussion continues on the respective roles of the committee and national authorities, on assessments of the suitability of the investigator and the facilities, on how a positive opinion might be reversed, and on the timing of an applicants response. Definitions are also needed for who can apply, in what languages, with what documentation, with what information to trial subjects, with what provision for declarations of the end of a trial, and with what date for its end.

 The issues include tying down which Good Clinical Practice rules are to be followed, including the legal status of the guidance, differences in respect of commercial and noncommercial GCP, updating of the ICH rules on GCP, and whether and how the EU guidance can be updated through annexes. Decisions are also needed on whether and how to permit the conduct of placebo-controlled trials, how to deal with borderline studies and products, observational studies, noninterventional studies, and who will be designated the responsible contact person.

 Issues include which documents must be submitted for evaluation, how closely they correspond to the headings under the clinical trials directive, whether there should be a limitation on the number of pages, how documentary requirements should correspond to successive phases of trials, how to provide for health volunteer trials, and the format for applications.

 Issues include the role of the member states and the EMEA in recording events and in evaluation, how to handle reports from non-EU countries, how to handle duplicate reports, arrangements for alerts, overall analysis, dialogue on safety concerns, electronic access, and line listing for short trials.

 The issues include the respective roles of the EMEA and the member states, whether databases should be separate or linked, what the user requirements will be, what amount of information they should carry, the extent to which the information should be available to the ethics committee, how to assure quality control, how to handle modification of data, what elements should be searchable, and what arrangements to make for noncommercial trials and for trials that do not start.

Other issues are still unresolved. Ethics committees must be composed of health-care professionals in the EU directive, but under ICH guidance the criterion is scientifically qualifiedleaving open the decision on who assesses what science means. There are unanswered questions on whether incapacitated adults may be included, on who should carry responsibility for indemnity and compensation, and on whether the assessment of the risk-benefit justification should be conducted by the ethics committee or the national authority. And should ethics committees have a role in trial monitoring and inspection? It is also still unclear what constitutes the significant or substantial changes that should trigger formal amendments to protocols. Other areas of uncertainty include rules for investigational medicinal products, inspection documentation and procedures and qualifications of inspectors, and safety reporting.

Arielle North, of the European Commissions pharmaceuticals unit, has added a further complexitythere is a distinction, she pointed out recently, between a detailed guideline (involving member states in a legal procedure under the EUs so-called comitology procedure, which operates via standing committees) and detailed guidance (which is discussed directly with member states without a formal committee procedure). This may seem like esoteric theologybut Brussels decision-making processes are full of these quirky complications about who can do what to whom and how often. The consequence tends to be more delay and more confusion.

Industry wants the system to be as efficient as possibleso, for instance, it says the documentation required by ethics committees and national authorities should be short and, as far as possible, the same, allowing companies to generate (and update) a single document that meets both needs. It says the GCP requirements should be covered by an enunciation of principles and a reference to existing ICH guidance. Informed consent requirements should be dealt with under the ICH GCP guidance, possibly with additional recommendations where necessary for special populations, but with no need for further or new guidance. And, it says, new pharmacovigilance requirements for clinical trials (currently being drafted by Germany on behalf of the Commission) should be in line with existing ICH and CIOMS principles and should limit annual reporting requirements to the substance itself, rather than imposing reporting requirements in respect of each country or protocol. Impending guidelines on manufacture and import requirements must, says industry, provide one standard in all member states and address the what and the why of controls, but leave the detail of how to the manufacturer.

According to Barry Arnold, MB, FRCA, FFPM, of AstraZeneca, a binding clinical trials directive is needed to ease the process for industry, because member states have been slow to implement many of the standardized procedures that have already been agreed at international level. The ICH guideline on expedited reporting of test results was implemented by only five of the 15 EU member states (France, Finland, Italy, Sweden, and the UK), despite the fact that it is already in force in the United States and Japan. Austria, Belgium, Denmark, Germany, Greece, Ireland, Luxembourg, The Netherlands, Portugal, and Spain are still operating on the basis of local legislation, with different rules and timelines. 

Some of these member states have refused to budge, because they had not themselves signed on to the guideline and did not accept that the Commissions signature on the ICH document was a sufficient base for them to act in line. But this impedes companies conduct of their clinical trials, alleged Dr. Arnold. The best safety data is collated data, so a standardized approach is desirable, and the clinical trials directive can help us and help improve public health, he said. Similarly, he pointed out, member states requirements on periodic reporting of investigational products continue to vary widely.

Meanwhile, there is anecdotal evidence that The Netherlands and Sweden are slowing down the start-up of trials. Local ethics committees are delaying central committee decisions, according to Guy Belcher of Takeda. But North says the Commission has already been obliged to back down from its original proposals to legislate on the type of committee that member states should put in place, and now it has no power to get involved at the local level. We cant intervene at member state level on how they organize their ethics committees, she admitted. Moira Daniels of AstraZeneca says she sees real problems in enforcement of timelines on the handling of submissions if member state authorities are not vigilantas she points out, individual companies will hardly want to be taking legal action themselves against local ethics committees.

Despite industry complaints, the Commission refuses to bring forward its planned consultation with the industry on all these important details. It is necessary for the Commission to obtain consensus on at least a core document among member states before opening the process up to consultation with the industry, says North. Otherwise it will become unmanageable. And so far, member states have been showing reluctance to abandon their own procedures for trial authorizationonly in recent weeks has a breakthrough occurred in moving towards acceptance of a single harmonized application format to be used in all member states. Until this point, there had been a real risk that companies would have to submit a single cover sheet with additional separate annexes for each member state in which they wanted to run the trial.

Daniels says industry is worried by the delay in agreement on the guidance for implementation of the directive. Companies are already setting up timetables for trials to start in 2004, but they are handicapped because they still do not have the information on how the EU rules will be operating at that time. 

We can meet the requirements, Daniels said, but we need to know. And while companies could, if necessary, put more resources into their clinical trials departments to deal with additional regulation, it had not been expected that the new directive would make compliance more complicated. We shouldnt have to increase the bureaucracy, she said.

Change may still be in the airbut in some areas it is taking too long to turn into clear rules for the industry to work by.            

View from Brussels

With the impending expansion of the EU and the revamping of current policies, the pharmaceutical industry is on edge, wanting to know what the future holds.

Applied Clinical Trials-04-01-2002

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A Rose by Any Other Name

European Change Is Still in the Air