We work so hard to recruit subjects for clinical trials, so why don't we try harder to retain them?		

Doug Engfer, cofounder and CEO of invivodata	

There is a lot of discussion about subject recruitment, but much less about retention. Why is that? When retention rates of 80% are considered "good," but dropout rates of 40% are common, there is definitely room for improvement. With that sort of dropout rate, a trial has to be at least 20% over-enrolled to compensate for the expected attrition.	

And there is clear financial incentive to focus on reducing dropout rates-the Medici Group reports that the cost of retaining a subject is one-third to one-fifth the cost of recruiting a new one.1 	

Subject retention seems to fall victim to our sense of immediacy and desire to measure results. While subject recruitment is fairly easy to measure and relatively immediate, subject retention is a protracted process that has traditionally been difficult to monitor because there were no real-time tools available.	

If retention can be improved, then subject recruitment goals can be lowered. Furthermore, if subject compliance is optimized, then the trial power will increase and again fewer subjects will be required.2 And if fewer subjects need to be recruited, the trial can be shortened, thus saving both time and money. In addition, the number of subjects exposed to an investigational agent is thereby reduced, a significant benefit in its own right.				

Generally, retention techniques focus on what I would refer to as rational or material inducements-gifts. However, I'd like to focus on some "softer," more emotional motivators that can pay real dividends based on our experience over the past several years.	

Researchers can improve subject retention by finding out what motivates them to participate in medical research. These motivations will govern their in-trial behavior. Harris Interactive ranks subjects' participation motives as follows: 				

For access to new treatments and to get better care for their disease or condition.

Once identified, volunteers' motives can be used to help retain subjects for the duration of the trial. Take subjects' lives into account when planning the trial design. Anticipate and accommodate their needs, building systems and protocols that work for them. Measure endpoints that are clinically important, but make sure that the subjects understand why you are evaluating those factors and that they make sense. Patient education is particularly important in placebo-controlled studies to ensure that the subjects understand that they may derive no benefit from the compound under investigation.				

In every trial, make sure that the burden on the subject is reasonable. Check to see if the number of visits, complexity of the tasks or physical distance from the site is influencing the dropout rate. And even more importantly, strive to maintain credibility with the subjects. If subjects learn that they can fabricate patient-reported outcome data, their commitment to the trial will be undermined.	

Training not only helps to ensure that subjects know what to do, but also why they are doing it. Communication and education help create a successful relationship between the researcher and subject, and will ensure that the trial achieves the best possible results.				

Frequent informed feedback can help reinforce positive behaviors and eliminate negative ones, especially if a subject-management system such as an eDiary is involved. However, the system and approach employed must accommodate the subjects' lifestyles, thus showing respect for them and their participation.				

In summary, remember to address the whole person-understand, appreciate, and support each subject's motivations to keep them engaged. If subjects are engaged both rationally and emotionally, then trial retention rates can be raised and maintained at higher levels, saving time and money in clinical research.	

1. The Research Roundtable, 3 (10) (March 2002). 				

2. Mckenzie et al., "Proving the eDiary Dividend," Applied Clinical Trials, 13 (6) 54–68 (June 2004). 	

Doug Engfer is cofounder and CEO of invivodata.	

Articles

A Closing Thought

We work so hard to recruit subjects for clinical trials, so why don't we try harder to retain them?

Retaining Subjects Is Harder Than Recruiting Them

In both oncology and cardiology, new EU rules correct some errors but leave others overlooked.

Progress marches on-and with it the regulatory framework. 

A new guideline should emerge from the European Medicines Agency by the end of this year to revise European Union guidelines on anticancer medicine evaluation in man.

 The revision will remedy an obsolete focus mainly on conventional cytotoxic compounds. 

What is striking about this is that the last revision is only a year old, and the initial guideline itself dates only from 2001. Regulations, like innovations, are made of fragile material. Science and technology now move forward so far in such a short time that a new approach is needed in designing clinical trials for many new treatments.

Toxicity, for instance, has for long been accepted as a surrogate marker for efficacy in early drug development. Most licensed anticancer medicines have had a narrow therapeutic index, so the mechanisms underlying toxicity are traditionally postulated to be the same as those promoting antitumor activity.

But new compounds targeting the activity of tumor growth factors, intra-cellular signalling, or structures in the tumor environment demand new approaches other than basic toxicity.

At the same time, some substances only work in combination with other compounds. And for substances targeting specific structures, such as constitutively activated enzymes, drug development focused on conventional "pathological-anatomical" indications might not always be regarded as the most appropriate. 

And new methodological questions are posed by the assessment of progression-free survival in open label studies, pivotal studies without a randomized reference, or the external validity of confirmatory studies.

For all these reasons, alternative designs of clinical studies are needed, says the concept paper on which the EMA is basing its work. New designs are to be suggested for exploratory studies making use of functional imaging or tissue biopsies (including molecular pharmacology) in order to define the pharmacodynamics of new compounds. And new mechanisms are needed for proof-of-concept studies when response rate is considered inappropriate or in case combined use of agents is needed to obtain anti-tumor activity.

The methodological issues to be addressed will include the use of historical controls in exploratory trials and choice of endpoints. Thought will be given to the role of external review and sensitivity analyses to reduce possible bias in open label confirmatory studies based on progression-free survival; and to possible bias comparing "cytostatic" and "cytotoxic" compounds with respect to progression-free survival. Other areas to be reviewed include external validity of confirmatory studies and special patient groups; rare tumors; appropriate comparators in confirmatory studies when there are evidence-based comparators and where there is not; and licensing based on studies without a randomized reference.

The next stage will be a late autumn discussion by the Agency's Efficacy Working Party and its Oncology Scientific Advisory Group.


The agency has moved faster on treatments for lipid disorders-another area where science and technology are moving the frontiers forward for clinical trials and treatment. It has just adopted new guidance on the evaluation of drugs for this indication,

 which will come into effect at the start of 2005.

Current mechanisms of disease categorization are too lax, the guidance says. The common classification of lipid disorders according to the prevailing laboratory abnormality "does not accurately represent the different genetic and metabolic defects, or clinical syndromes." Blood lipid levels may be affected by other clinical conditions such as diabetes mellitus, thyroid disorders, or nephrotic syndrome, so underlying conditions should be treated, and lipid levels should be reassessed once the disease has been controlled.

The guideline defines the primary goal of treating lipid disorders as prevention of cardiovascular morbidity and mortality associated with lipid levels-although it recognizes that in rare cases of very high triglyceride levels, the initial aim is prevention of acute pancreatitis.

The advances have been dramatic in this field, the guideline acknowledges. For instance, most HMG-CoA reductase inhibitors have been shown to reduce cardiovascular events (including stroke) and overall mortality in patients at high cardiovascular risk, irrespective of their cholesterol levels. Some data also suggest that fibrates have been shown to reduce the rate of coronary events both in patients with mixed hyperlipidemia and in men with coronary heart disease with only low levels of HDL cholesterol without hypercholesterolemia. 

Nevertheless, in the regulator's role of doubting Thomas, the agency points out that "positive effects on mortality and morbidity can only be evaluated properly in large-scale and long-term clinical trials, in patients with lipid disorders and/or high cardiovascular risk." And until this data is available, it should be specifically mentioned in the product characteristics that beneficial effects on mortality and morbidity are unknown.

Some small concessions are made to the realities of developing new treatments. A relative reduction in LDL cholesterol is acceptable in patients with primary hypercholesterolemia as a valid surrogate endpoint, provided that no claims are made regarding morbidity and mortality. But it sharply reminds that "ideally a new lipid-modifying agent is expected to demonstrate an effect on the prevention of cardiovascular morbidity and mortality."

And reduction in triglyceride levels and/or increase in HDL-cholesterol might also be considered as a relevant component of the primary endpoint for particular target populations. "However," it insists, "an isolated effect on these parameters is in principle not expected to be the sole basis for the demonstration of the efficacy of a new lipid-modifying agent, but should be seen in conjunction with the effect on non-HDL cholesterol and the underlying mechanism as well."

It is also cautious on assessment in terms of effects on vascular damage. Although target organ damage of heart, brain, kidneys, and blood vessels is "presumably and plausibly" associated with morbidity and mortality, "the prognostic value of these drug effects with regard to morbidity and mortality remains to be established," it says. The agency is particularly skeptical over changes in intimal media thickness and plaque stability.

The best it can offer is the prospect that such studies may become more useful in the future. "These endpoints can be particularly valuable for the scientific community as they may bring information on how the medications act and can have clinical protective effects. As more becomes known, such studies may substitute clinical studies using hard clinical endpoints in selected subgroups."

Planning for a mortality study factors in all-cause mortality and/or cardiovascular mortality, as adjudicated by a blinded, independent committee. If cardiovascular mortality is chosen as a primary or co-primary endpoint, effects on noncardiovascular mortality should also be considered. And the evaluation of cardiovascular morbidity should especially take into account signs and symptoms of organ damage (such as myocardial infarction or stroke) and their therapeutic management. An unqualified veto is also placed on placebo-controlled trials, since there are now effective treatments available.


Evaluating the effects of a new agent for treatment of lipid disorders will generally require a study on the type of lipid disorders for which the drug is intended. Studies for the evaluation of efficacy or safety of a new lipid-modifying agent are mainly performed in subjects with primary hypercholesterolemia and mixed hyperlipidemia with moderately to very highly elevated cholesterol levels. Attention should be paid to effects of gender, race, and age. Subjects with clinical and/or other manifestations of atherosclerosis and/or type 2 diabetes mellitus should be represented in adequate numbers to allow statistical (sub)group evaluation. 

The guideline urges no radical departures in strategy design for studies of the first administration of products for lipid disorders to man: they should not differ essentially from those dealing with other cardiovascular products. Following initial screening, a dietary lead-in period is obligatory before randomization in the study. Inclusion criteria and the reliability of the methods used should be justified, taking into account such factors as the target population and assay accuracy.

The progress in science, technology, and clinical trial design makes possible new therapies-but also means continual production of new rules and guidelines. 

Meanwhile, the chief European Union regulators are going to be changed at the end of October (see sidebar below). The senior figures in the European Commission, the civil service of the EU, are being replaced: out goes Commission President Romano Prodi and nearly all his team. In comes Jos Manuel Barroso, until now the prime minister of Portugal, and 24 colleagues from across the enlarged EU.


1.CHMP/EWP/l068/04: Recommendation on the need for revision of the CPMP note for guidance on evaluation of anticancer medicinal products in man; http://www.emea.eu.int/pdfs/human/ewp/106804en.pdf.

2. Note for guidance on clinical investigation of medicinal products in the treatment of lipid disorders, CHMP, July 2004; http://www.emea.eu.int/pdfs/human/ewp/302003en.pdf.

SIDEBAR: Key figures in the new European Commission

 from Germany, responsible for industry affairs-including enterprise policy, competitiveness, and the European Agency for the Evaluation of Medicinal Products
  

 from Greece, responsible for environment-including questions over genetically modified products
  

 from Slovenia, responsible for science and research, including the EU's joint research centre and the EU's multibillion euro research budget 
  

 from Cyprus, responsible for health and consumers protection, and in charge of the new European Centre for Disease Prevention and Control, which is shortly to open up in Stockholm
  

 from Ireland, responsible for questions relating to access to the 25-state single market that the EU now represents
  

 from the United Kingdom, responsible for trade, including cooperation (and dispute resolution) with the United States and Japan


View from Brussels

New Guidances Try to Keep Up with Progress

The right person can successfully promote proper management of quality and compliance, leading to desired clinical trial outcomes.

The purpose of this article is to propose a role called "quality coach," an independent expert dedicated to system and project quality, as a member of teams implementing software applications to support clinical data management activities. The article presents the issues unique to the regulated environment in which the software project resides, and explains the advantages the quality coach role brings to the team and the accomplishment of its goals. The concept of a quality coach is new and unproven. However, the authors have informal feedback from one company's widespread efforts that there are benefits, and look forward to interviews and surveys to fine-tune the concept in the future.

Regulatory agencies have encouraged the use of electronic records in clinical trial research. Such records offer advantages for data management, communication, and processing. However, along with these advantages come concerns. If it is easier to manage the data, it is also easier to mismanage the data, whether intentionally or accidentally.

Enter the regulators to ensure that adequate controls are in place to either preclude or identify mismanagement. The control mechanism is typically a combination of system validation, an audit trail, and a set of SOPs. The goal of the control mechanism is always the same-to reduce the probability of negative outcomes and make such occurrences highly visible.

At the most basic level, the risks of using electronic records in clinical research fall into two categories. The first category includes risks that endanger the utility of the data. Data corruption can be caused by inadequately tested systems or by individuals with criminal intent. If the data cannot be used to make decisions about the safety and/or efficacy of a drug compound, then the effort spent to collect that data will have been wasted. The FDA has set forth its expectation that data be attributable, legible, contemporaneous, original, and accurate.

The second risk category includes risks that endanger our ability to know and replicate the life story of the data. If we cannot describe what happened to our data, when it happened, and the actors and actions that caused it to happen, then we are not in control. If doubts should arise concerning data quality, we have no mechanism for reviewing data history and either alleviating or confirming doubts. If lack of control is pervasive we have reason to doubt data quality, even if no other specific reasons have raised questions about the data.

The design of computer systems that manage clinical data-for all or part of a life cycle that typically includes creation, modification, maintenance, archiving, retrieval, and transmission of records-must be a process that is permeated by awareness of the two noted types of risks. Features and safeguards must be implemented that protect data quality. And given the possibility that unforeseen circumstances may compromise those features or safeguards, there must be mechanisms in place that assist the system owner in identifying failures, understanding how they occurred, and preventing repetition in the future.

What are the possible ways to implement these safeguards? Who is in the best position to take on the responsibility for this implementation? Let's look at the qualifications of such a person. He or she must be knowledgeable in several areas:

 Its importance to the business process, along with specific system requirements and functions, and risks associated with its malfunction.

 The flow of the data in the system; the actions performed on that data, and risks associated with failed or incorrect actions; the different types of electronic records managed by the system, e.g., CRF data, consent forms, laboratory data, etc.

 The relevant rules and guidelines for clinical data records and the systems that manage such records, e.g., 21 CFR Part 11, corporate SOPs, etc.

 The steps involved in delivering a computer application system; familiarity with the quality issues related to the steps; general knowledge of computer systems validation and its associated deliverables.

It is unrealistic to expect a single individual will have in-depth expertise in all these areas. A team approach brings together people whose shared knowledge covers the required areas sufficiently to support the development project. Focusing on key requirements helps to identify the members of the team required to implement, monitor, and manage safeguards. 

Knowledge of the system and its data tends to reside in a designated system owner. The system owner is ultimately responsible for ensuring that the system meets the requirements of the business process. Also, this individual is responsible for ensuring the quality of the system, including compliance with regulatory requirements and corporate SOPs.

In-depth knowledge of the software development process resides in a project manager. This individual maintains a project schedule and a catalog of expected deliverables, monitors progress, conducts project meetings, and addresses the issues that arise. Because computer systems validation is an important component of a good software development life cycle methodology, the project manager is responsible for including validation-related activities in project plans. This individual must ensure risks are assessed; required team members are appropriately assigned; sufficient funding is secured; processes are defined; and specifications, validation scripts, and summary reports are defined and documented.

Every software development project presents unique issues regarding validation, quality, and regulatory compliance. Special analysis and decision-making are required to manage these issues. A project manager, even though familiar with the general concepts and deliverables, may not have the required breadth of experience and in-depth knowledge of the regulations. Further, a system owner will likely be managing competing priorities and be focused on taking delivery of a completed solution with implicit expectations regarding quality of a production system.

Providing a quality coach to support the system owner and project manager can be a successful approach for ensuring the proper management of quality and compliance requirements. The quality coach is an active member of the project team, responding to questions from other team members. The coach initiates discussions on quality and compliance topics and guides activities that lead to successful resolution. The quality coach can advise by reviewing documents and procedures. The coach is part of the group that approves two fundamental documents-the Validation Plan and the Validation Summary Report-and may be involved in approving other documents, such as user requirements, functional specifications, and/or technical specifications.

The involvement of the quality coach in the writing of the Validation Plan and the development of the risk analysis establishes the importance of the role early in the project. Working in partnership with the project manager and the system owner, the quality coach earns recognition as a resource across all phases of the project. In addition, the quality coach creates a firm foundation to understand and evaluate the concepts of risk, control, validation, evidence, and credibility. Placed in the proper context through effective communication by the quality coach, these concepts will serve as the backdrop for all ensuing project activities. These concepts will impact the way the project team executes daily activities and will become second nature when the team members talk and think about their tasks. 

The issue of objectivity is important when implementing a quality coach role. The quality coach is part of a team, but also a reviewer and approver of team activity. The quality coach must walk the thin line between supporting team efforts and imposing quality-related requirements. It is the job of the quality coach to make the thin line disappear by convincing team members that quality-related standards belong to everyone and are an essential part of goal achievement. The system owner is typically the person ultimately responsible for the quality of a system. The quality coach helps the system owner assess the risks associated with quality issues, which become the basis for key planning processes. The system owner and quality coach agree on an approach to managing risks that makes best use of available resources. 

There may be situations in which the objectivity of the quality coach comes into conflict with the priorities of the system owner. The compliance activities recommended by the quality coach may be unacceptable to the system owner due to budget costs or schedule delays. The system owner makes the final decision, accepting responsibility for the potential negative outcomes. Validation and project documents should describe the differences in opinion and the decisions made. The quality coach can sign the relevant documents for accuracy, even though he does not support the decisions that were made. In reality, this scenario is unlikely to occur if the quality coach does a good job of educating project personnel regarding the importance of quality and compliance and the risks of ignoring regulatory requirements, SOPs, or best practices. 

The identification of risks is a task in which the quality coach can play an especially valuable role. Ask a system owner or project manager "Where can things go wrong?" and you will probably be met with silence. The dialogue needs structure, and the quality coach can bring focus, sequence, and clarity to the discussion. The quality coach's knowledge and experience, gained from a variety of software development projects, can counter the unfamiliarity and discomfort with an infrequently done task that may be felt by some team members. With appropriate questions, examples, and explanations, the quality coach can help the team members understand risks , likelihood of occurrence, and the level of difficulty in detecting them.

The quality coach's role must also be distinguished from the role of a formal quality assurance (QA) department. The QA department may perform audits, enforce regulatory compliance, and identify the entire set of compliance problems for a particular system. Throughout the software development life cycle, the quality coach educates the project team on compliance issues, maintains constant vigilance for emerging quality issues, and proposes solutions for the problems discovered. The goal of this involvement is to set the stage for successful completion of the QA/validation process.

Similar to poorly defined user requirements for an application that takes on additional functionality and suffers from "scope creep," a quality coach must be vigilant and avoid "role creep." For example, a quality coach who wants to see project success might take on some of the project manager's responsibilities. This altruistic behavior can lead to negative outcomes. The quality coach's objectivity may become compromised, or his ability to meet the demands of other assignments may be undermined.

The implementation of a quality coach role offers the opportunity for improved compliance planning across the organization. Quality coaches from separate development projects can meet regularly to share experiences, suggest solutions, and improve the services offered by quality coaches across all software development projects. In addition, a group of quality coaches can serve as a resource to a formal quality assurance department or to a group responsible for setting policy and standards for computer systems validation or other quality and compliance activities.

Is a quality coach needed for every software development project? Probably not. A small, tightly focused application may present a narrow range of quality and compliance issues that do not require such a focused role. A project manager may be able to address some of these issues with the quality assurance department. However, a more comprehensive application, with greater complexity, could reap the benefits of a quality coach participating on the project team.

EdD,* is associate director, technology and quality control, with Johnson and Johnson Pharmaceutical Research and Development, 920 Route 202, Raritan, NJ 08869, (908) 704-4993, email: icantor@prdus.jnj.com.

MS, MBA, is manager of IM quality and compliance for J&JPRD, Raritan, NJ, (908) 704-4370, email: mlink@prdus.jnj.com. 

SM, is principal of Michael B. Weis Consultancy, P.O. Box 414, Ringoes, NJ 08551, (609) 466-1261, fax (609) 466-9353, email: michaelbweis@aol.com.

*To whom all correspondence should be addressed.			

Feature Article

The Quality Coach

Handbook of SOPs for Good Clinical Practice, Second edition
Celine M. Clive (Interpharm/CRC Press, 2004), 288 pages with CD-ROM, hardcover, ISBN: 0849321816, $229.95

Handbook of SOPs for Good Clinical Practice was prepared as a tool to aid organizations in the development of standard operating procedures (SOPs) for groups involved in the conduct of clinical trials. It is a revision of an earlier version of the handbook prepared by different authors. The book is divided into three sections covering SOPs for the sponsor and/or contract research organization, the study site, and the institutional review board (IRB). In addition to providing templates of standard SOPs that can be customized and adapted for use, the book also contains examples of common forms and checklists that are useful in the implementation and execution of the SOPs. Another advantage of the book is the inclusion of a CD-ROM that contains an electronic copy of all of the templates and forms for ease in preparing the customized versions for personal use. 

The book is a very basic resource and contains only the minimum set of SOPs that an organization would need to cover activities related to the execution of a clinical trial. It also lacks any kind of explanation of the origin or genesis of some of the SOPs and the roles of persons described. And as a result, the book might be a better resource if accompanied by some discussion of what GCP is, how it is applied, and the role of different individuals. The book also makes numerous assumptions without explanation regarding the organization and role of individuals involved in the clinical studies. Many of the SOPs contain statements regarding GCP practices that are not supported, nor consistent with most interpretations of GCP. For example, the SOP for the Sponsor regarding study clinical supplies refers to interactions with the site pharmacist only. This assumes that all sites have a pharmacist on staff. The SOP discusses the role of the monitor, pharmacist, and coordinator, but never mentions the role of the Principal Investigator-who is ultimately responsible for the clinical supplies, regardless of whether there is a site pharmacist available. The SOP regarding obtaining informed consent directs the coordinator to contact the IRB and ensure that the draft is compliant with the regulations. This is clearly a task that is the regulatory responsibility of the Investigator. This SOP also indicates that a witness is required for informed consent when a non-English speaking person signs the consent, also not required by GCP.

Despite some of these deficiencies, Handbook of SOPs for Good Clinical Practice is a good beginner's reference for someone who needs to prepare a set of SOPs.

PhD, is with Moriah Consultants, Yorba Linda, CA, email: michael@moriahconsultants.com.

Media Review

Celine M. Clive (Interpharm/CRC Press, 2004), 288 pages with CD-ROM, hardcover, ISBN: 0849321816, $229.95

Handbook of SOPs for Good Clinical Practice, Second edition

This new software for patient-reported outcomes has a host of capabilities, and a novel device to house it, too 

(Pittsburgh, PA) new SitePRO software uses a unique device originally invented to take notes. 							

			The medium is the message, the saying goes, so a new media needs a new message. In this case, the new media is 

 (Los Gatos, CA) Danaâ¢ device, a full-size keyboard with an attached LCD screen on top that looks like either the world's biggest PDA or the world's smallest laptop. The new message invivodata brought was SitePRO, an in-clinical patient reporting system for patient-reported outcomes. 				

				The familiar keyboard allows anyone to use it with relative ease. The display is much wider than a PDA, and allows users to type in responses or to tap the touch-screen. Importantly, the large display also means that complex questions can be asked entirely on one screen without having to rephrase  or run onto a second page. And since the PRO entries are the original data straight from the subject, there are no data entry errors.			

				Such keyboards offer the price of a PDA and the comfort of a laptop, all at two pounds: the weight of a quart of milk. And the subjects' data is scored automatically, letting site staff deal with discrepancies right away.			

QuickSTAT offers access to a database of drug delivery—the kind that involves a van and an invoice slip

 (New York, NY) is a division of Quick International Courier, which has over 20 years experience handling critical shipments for all industries. For clinical trials, QuickSTAT created the Quick-OnlineRx online order entry system. This password-protected system simplifies the process of creating shipping paperwork and notifying QuickSTAT of a specimen pick-up at the investigator site level. 

QuickSTAT ensures the timely delivery of critical patient specimens and provides the same level of service for study drug deliveries. As the industry knows, a change in temperature or a late arrival can cause a domino effect that turns into millions of dollars of extra cost.  

Customers who use QuickSTAT know that their time-critical shipments will move through a tight transportation loop. The QuickOnlineRX system notifies all of the key players involved with the study with advisory communications even if unforeseen delays affect delivery status. Proof of delivery is automatically emailed to all parties when an important package gets delivered. 

QuickSTAT staff include customer service, operations, and dangerous goods staff who are trained specifically on the needs of the biopharm community. 

Cold Chain has developed a cool way to ensure your sensitive shipments don't get too hot or too cold

(Holliston, MA) developed a smart thermometer that will squash any worries about a product being shipped. 

The KoolWatchâ¢ temperature monitor is a purple-and-yellow card smaller and lighter than an empty Tic-Tac box. It blinks "OK" so long as its sensors don't detect a rise or fall n temperature beyond its preset highs and lows. In addition to clinical supplies, pharmaceuticals, and vaccines, it's also used for perishable foods and chemicals.   

There are many steps in a transfer from the manufacturing plant to the hands of the subject. Having a KoolWatch thermometer riding alongside the package will give confidence that the package temperature stays as compliant as, ideally, the subjects going home will be when they take their medicine. 

The battery inside lasts for up to three years in storage and then two years in actual use. It can be reprogrammed for different parameters, and comes with double-sided tape to stick to packages. They run as low as $5 each, when bought in cases of 50. 

eShowcase

invivodata's SitePRO,? QuickSTAT's QuickOnlineRx,? and Cold Chain Technologies' KoolWatch?

A standardized subject retention and adherence system helps study staff focus on critical details during all phases of a large, simple trial.

Aside from recruitment, one of the most difficult activities in clinical trials is maintaining a participant's adherence to the study protocol. Studies show that lost adherence is most commonly related to troublesome life circumstances (65%), with an additional 20% related to adverse effects and 15% related to intercurrent illnesses.

 By taking the squared function of estimated sample size, trial design allows accommodations for adherence that will be predictably lost. For example, 80% adherence would require an almost 60% increase in sample size, while 50% adherence requires a four-fold increase in sample size.

 Losses beyond these original assumptions will adversely affect a trial's original design. In a long-term trial following thousands of participants, the issue of adherence and retention is magnified.

A recent practiced-based, randomized, multicenter clinical trial following 42,418 high-risk hypertensive participants responded to this issue by assembling existing adherence tools into a single reference resource called the Adherence Survival Kit (ASK). Many of these tools were based on proven adherence concepts, while others were developed in direct response to the distinct and evolving needs of the study clinics.

 The ASK binder was divided into nine sections organized around the four key adherence goals set by the trial leadership (see Table 1). This report presents a detailed account of the development of the ASK, a rationale, and description of the materials included.


The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a practice-based, randomized, multicenter clinical trial of pharmacological antihypertensive treatment, and in a subset, cholesterol-lowering treatment. ALLHAT followed 42,418 high-risk hypertensive participants who were 55 years and older and had at least one additional risk factor for coronary heart disease. Participants were randomly assigned to receive one of four pharmacological treatments: chlorthalidone, amlodipine, lisinopril, or doxazosin. Supplemental open label therapy was available for participants who did not meet the treatment goal of blood pressure less than 140 mm Hg systolic and less than 90 mm Hg diastolic on monotherapy. Follow-up visits took place quarterly for one year, and thereafter three times a year for an average of six years.

 The doxazosin arm of the study was discontinued early in 2000 based upon two factors: the low likelihood of observing a significant difference in the primary outcome by the end of the trial; and a significantly higher incidence of major cardiovascular disease, especially congestive heart failure, in the doxazosin arm compared with the chlorthalidone arm.

ALLHAT participants were enrolled by more than 600 clinics in the United States, Canada, Puerto Rico, and the U.S. Virgin Islands. Of these, 65% were private or group practices, HMOs, or community clinics; 23% were Veterans' Affairs (VA) or university medical centers; and 12% reported their clinic classification as "other."

 Over half of the clinics conducting research for ALLHAT were primary practice clinics.

These clinics experienced many factors that adversely affected their ability to maximize adherence at their clinics. Since ALLHAT did not provide direct support for clinical research staff at any of the clinical sites, staff members with limited research experience were trained to conduct the study at many of the private care facilities. Additionally, recurring employee turnover during the conduct of the trial necessitated repeat training of clinic staff. Further, the evolving health care needs of the aging ALLHAT population required many participants to seek care from non-ALLHAT physicians and specialists who may not have been willing to adhere to the ALLHAT protocol.

While ALLHAT was designed to allow accommodations for predictable losses in adherence, losses beyond the original assumptions of the trial would threaten the success of the study.

 The recognition of the challenges faced by the ALLHAT clinics, and the long duration of follow-up, resulted in concerns that adherence would become an increasingly greater challenge as the trial progressed.

By January 1998, a decline in overall adherence was notable. For example, approximately 10.5% of participants at 12 months of follow-up had missed two or more of their most recent consecutive study visits. This number increased to 14.6% at 24 months. During the same periods, 15.6% and 19.2% of the participants had stopped blinded study medication. To address this, the NHLBI Project Office and the ALLHAT study leadership adopted four key adherence objectives: 1) keep participants on their study medication; 2) conduct a study visit with each participant three times a year; 3) keep blood pressure controlled below 140 mm Hg systolic and below 90 mm Hg diastolic; and 4) report all study events.

While the four key adherence objectives were straight-forward, assisting the clinics in achieving these goals proved to be a considerable challenge for the study leadership. During the conduct of the study, many adherence tools were developed to address the needs of the ALLHAT clinics. Many of these tools were based on proven adherence concepts, and others were developed in response to the evolving needs of the clinics. Each of these tools had been distributed to the clinics at different times during the start-up and follow-up phases of the trial, resulting in inconsistencies regarding the availability of these tools across the roughly 600 clinical sites. ALLHAT's Retention and Adherence Subcommittee assembled the Adherence Survival Kit (ASK) to consolidate all of ALLHAT's adherence tools into one resource, developed to uniformly distribute these tools to the ALLHAT clinics.

The ASK binder was organized to direct the user to the tools that addressed their most pressing retention and adherence needs. These tools assisted clinics with limited research backgrounds, while providing innovative ideas to more experienced clinics that were also struggling to maintain the study protocol and reach adherence goals. Further, a distribution strategy was developed to provide the ASK resource to each site and optimize its use among the diverse clinics without a central training session.


The introduction section of the ASK presented basic adherence concepts to the clinics in an effort to educate and reinforce the importance of participant adherence and retention as an operational issue in clinical trial management. Inexperienced clinic staff was encouraged to use these tools to develop procedures that would decrease the number of lost participants at their clinics. More experienced clinic staff used these materials to review and reinforce their existing procedures for maintaining contact with participants.

These materials included "Adherence: A Short Course," from the Handbook of Health Behavior. While this had been used in previous clinical trials, it was adapted to ALLHAT and included in the introduction of the ASK.1 The course summarized five key points of successful adherence: 1) identifying threatened or reduced adherence; 2) addressing incomplete protocol adherence; 3) maintaining adherence in the majority of participants; 4) using an adherence team approach; and 5) assuring minimum adherence.

The "Red Flags" check list from the same work was provided to help clinic staff identify early warning signs of participants at greatest risk for reduced adherence. The list also highlighted specific behaviors and signals that a participant who is at greatest risk for being lost might demonstrate. Clinic staffs were encouraged to place copies of the checklist in each participant's chart for use during clinic visits.

The introduction also had a short description of the four key adherence goals of the study, followed by a step-by-step guide on how to use the ALLHAT monitoring reports. These reports were distributed monthly to both clinic and regional staff, and were developed to help manage participant activities and identify possible adherence problems.


Because of the aging study population, fulfilling the protocol elements was threatened by hospitalization for acute and chronic conditions, as well as the transfer of care because of declining health or changes in health insurance. Movement of participants between states, especially during the winter months, also presented challenges to collecting data within each study visit period. Some study participants developed clinical trial fatigue and lost interest in the study due to its long duration (six years). In response to these factors, the committee needed to find ways to prevent the resulting attrition. Therefore, tools were designed to fill the need of tracking participants without significantly increasing the study workload of clinic personnel.

Materials in this section of the ASK included retention posters developed by ALLHAT staff. These posters were made available to clinical sites to be strategically displayed in the clinic as a continued reminder of the study to the participants. Appointment cards and visit reminder postcards were provided so that participants did not have to commit appointments to memory. These cards also reminded participants to bring their study medication, and specified whether or not the upcoming appointment required fasting for laboratory tests. 

To collect contact information that is often not centrally located in the clinic chart, a participant contact information form was designed. This contact information form was completed by the participant and updated yearly. In addition to the form requiring that the participant list his/her own address and telephone number, the form requested the contact information for two additional friends or relatives not residing at the same address as the participant. 

Six letter templates were also developed in response to many of the issues faced by study coordinators. The letter templates could be easily copied onto clinic letterhead for immediate use, or an electronic version of the templates could be requested to allow adaptability for the individual needs of a clinic. Some examples of these letters included: a request to participants who had missed two consecutive visits to re-establish communication with the ALLHAT clinic; a description for non-ALLHAT physicians explaining the importance of the trial and requesting their cooperation; and a request to participants who had entered a nursing home to maintain contact with the clinic.

A postcard visit was developed for those participants who had an extended absence from their hometown and could not make scheduled in-clinic visits. The postcard could be given or sent to participants, completed by the participant within a set time period, and mailed back to the clinic. Data from the postcards were transferred to the appropriate case report forms for submission. Other tools included a tip sheet on how to transfer a participant to a new ALLHAT clinic and a "Participant Party Kit," which was an event planner for use in enhancing participant education and social networking among participants.


All ALLHAT study events required appropriate medical documentation. Since many participants had multiple sources of care, documentation was often collected from hospitals and medical providers other than those familiar to the ALLHAT clinic. Study coordinators found that letter templates and medical release forms helped reduce the amount of time needed to prepare medical records requests, and increased the likelihood of receiving the requested documents without additional paperwork, requests, or telephone calls.

The collection of death certificates was also difficult for many ALLHAT study coordinators. State laws governing confidentiality made the retrieval of a death certificate difficult in many states. Plus, ALLHAT's international enrollment meant that the study needed access to death certificates from each of the 48 continental states as well as Puerto Rico, Canada, and the U.S. Virgin Islands. State approval under the National Death Index (NDI) helped to facilitate requests made by the clinic staff on behalf of the study. Letter templates helped study coordinators request these documents from government agencies, hospitals, medical providers, and family members.

In order to facilitate obtaining necessary hospital records, a template for a "Release of Information" was included in this section. This template allowed staff to photocopy the document onto clinic letterhead, have it signed by the participant or his/her next of kin, and then use it in obtaining medical documentation needed by the study. Clinics were instructed to update this release on a yearly basis. In order to expedite requests for hospital records, a letter from the National Heart, Lung, and Blood Institute's ALLHAT Project Office, which explained that the request was for research purposes, was provided to the sites to be included in their requests for medical records. To assist in collecting hospital records or death certificates for deceased participants, a compassionate and professional letter template was included to gather information and permission from the family.

Because of the specific application and approval process for NDI, letter templates were provided for requesting death certificates from state agencies. These documents specified the ALLHAT NDI approval number that identified the request as part of research and facilitated the retrieval of documents from state agencies. Telephone numbers and fees for all state agencies responsible for handling death certificate requests were also included, along with suggested tips on how to best obtain death certificates. Additionally, "tip sheets" were included to assist study coordinators in identifying study events, completing study event forms, and collecting medical records and death certificates.


As in many large, multicenter trials of long duration, the ALLHAT population encountered many obstacles in maintaining medication adherence for participants. The primary focus of this section was to educate inexperienced staff and increase their comfort level when managing an ALLHAT participant's medication regimen. This included treatment procedures that could be reviewed quickly, and materials for the participant on the importance of adherence.

This section of the ASK included scripts that were written to give study coordinators step-by-step suggestions on conducting a study visit, including event ascertainment and medication adherence. This section included a drug rechallenge algorithm as well as a restart plan to help staff identify those participants who might be most successful at beginning study medication again. Also included were strategies for working with non-ALLHAT physicians who were assisting ALLHAT participants to keep the subjects on their assigned study medication.

Since participant cooperation is the primary factor in adherence to study medication, ALLHAT published material intended for study participants. An ALLHAT participant newsletter included current study information and was circulated semi-annually. A special edition of this newsletter was developed to help participants remember and understand the purpose and importance of the study, and encourage adherence to their assigned study medication. In addition, a semi-annual participant flyer was initiated to communicate ideas about adherence to the study protocol in lay terms. Examples of the flyer and the special edition newsletter were included in this section of the ASK.


Many of the same issues impacting adherence and retention measures also affected blood pressure. Reinforcement of the blood pressure goal, and use of ALLHAT's first and second line drugs to effectively manage a participant's blood pressure, were incorporated into the ASK. 

Materials in this section were generated from the protocol and Manual of Operations, and were reformulated to offer an accessible dosing schedule and algorithm reference source to ALLHAT staff members. The dosing schedule was printed on a pocket-size laminated card that included the blood pressure goal, a step-by-step description of how to increase the dose of study medication and/or add supplemental medications to control blood pressure, and a table identifying the ALLHAT doses and equivalent doses of each medication. The card provided a different manner of viewing the step-by-step increase of medication to reach the blood pressure goal. For convenience and quick reference, the dosing schedule, algorithm, event reporting, and medication tips were also developed on a pocket card.


Bonding between study coordinator and participant often occurs during a study, and can be the cornerstone of successful adherence and retention. However, this relationship is often difficult to maintain in the constantly changing nature of today's medical environment. This section of the ASK included suggestions to enhance the relationship between the clinic staff and the participants.

These were compiled in a list focused on making the study visit more convenient for the participant (i.e., how to reduce the time for each study visit) and on making the participant feel more comfortable. Formats for birthday cards and study participation anniversary flyers also provided opportunities to contact participants outside of a visit and acknowledge important events in their lives, besides their study involvement.

Scientific resources/frequently asked questions


Although much of the scientific literature on participant adherence and retention in clinical trials is anecdotal, some data and factually based reports are worthy of note. Copies of published reports were provided to clinical staff so that they could study these in greater detail. The objective was to provide clinical staff with a small but comprehensive collection of articles to help them understand and formulate plans to maintain and improve participant adherence and retention.

Articles provided in this section of the ASK were Follow-up and Adherence in Clinical Trials of Elderly Subjects by Applegate.

 The final results paper from the Treatment of Mild Hypertension Study provided documentation of the low frequency of adverse effects related to the study medications used in ALLHAT.

 The ALLHAT study design paper was also included so that clinic staff could reference the intent, focus, and importance of the study.

 An article from Urban Cardiology was included to further explain the importance of ALLHAT and its successful completion, particularly in reference to minority patients.

 Finally, questions and answers from a featured discussion session during the 1997 ALLHAT Investigators' meeting were included as a review of relevant protocol issues.


Since many study coordinators focused their efforts on maintaining active participants and devoted little effort to recovering lost participants, the number of participants lost to the study grew over time. As planning for closeout began, another section was added to the ASK to help coordinators with the difficult task of finding and maintaining contact with lost participants.

This process included identifying participants who were mislabeled as refusing further study participation, when in fact they were only refusing to take the study medication or refusing to attend clinic visits. Because re-establishing contact with lost and refusing participants was imperative for obtaining closeout information and vital status of the cohort, the kit provided tools to find lost participants and formerly misclassified refusals. The ASK also provided ideas on effective methods of contacting participants, and maintaining the participant's interest after re-establishing contact.

Internet and computer searches were an important resource for finding lost participants. In order to help educate study coordinators on how to utilize this technology, a Web resource and computer search guide was included in this section of the ASK. A worksheet helped coordinators keep track of the information gathered during these searches. A telephone script summarizing challenges and alternatives aided in obtaining the most information when conducting telephone conversations with participants or their family members. Once a participant was found, it was important to maintain contact. For this focus, "Tips to Remember When Recovering Lost Participants" was included along with a list of ideas to enhance and maintain participant adherence. An additional resource was a letter template designed to capture the attention of nonresponding participants. Finally, a list of local volunteer organizations was included, along with ideas on how to utilize volunteers to help with the study. 


Study clinics in Puerto Rico and U.S. regions with large Spanish-speaking populations needed ASK resource materials in Spanish. This section included samples of all adherence materials that were made available in Spanish, so all study coordinators with Spanish-speaking participants had appropriate materials readily available. Materials provided in Spanish included: retention posters, contact information forms, visit reminder postcards, missed visit postcards, all letter templates, release of information forms, special edition participant newsletters, and the Participant Party Slides.

Distribution and implementation of the ASK


Key elements of the ALLHAT adherence strategy were to facilitate the uniform distribution of the ASK and to successfully motivate the clinics into using the adherence tools. Initially, the Retention and Adherence Subcommittee set out to introduce the ASK during face-to-face meetings. These sessions would allow the regional coordinating staff to highlight specific tools offered in the ASK that would be most beneficial in dealing with issues specific to each clinic. The nine Regional Coordinating Teams introduced the kit to some of the clinics during specially organized working lunches, dinner meetings, teleconference calls, or individual site monitoring visits. Distribution to some clinics was accomplished during regional sessions of the April 1999 Investigators' Meeting, where many aspects of the ASK were featured in both plenary and breakout sessions. Reinforcement of key elements was accomplished during subsequent regional and national investigator meetings.

This distribution strategy resulted in active discussion and problem-solving of medication and blood pressure issues between clinic investigators and ALLHAT leadership, producing a greater understanding of the study goals during the follow-up phase of the trial. Individualized distribution of the ASK was done collaterally with discussion of specific adherence problems encountered during telephone or face-to-face visits, creating an environment for positive interaction between the clinics and the study. The result was more purposeful and constructive interaction between the study leadership and the clinics during a crucial time in the trial.


Development of the ASK grew out of the need for ALLHAT clinics to maximize participant adherence to the study protocol. Since the focus of many of the ALLHAT clinical centers was primary care, routine adherence activities (appointment reminders, conducting appointments within study visit periods, tracking and finding lost patients) fell outside their normal work scope. This lack of basic adherence understanding, coupled with the research naivete of the clinical centers, led the study leadership to develop the ASK. The ASK was an organized and consistent approach to the execution of the study protocol. This comprehensive approach included overall adherence goals with an emphasis on prevention and specific approaches to participants who exhibited any level of reduced adherence.In the winter of 1999, a questionnaire was developed and distributed to those clinics who had been provided with an ASK and were still actively involved in ALLHAT (n = 544). With a 78% response rate, the survey revealed that 77% of clinics felt that their adherence issues were addressed by the ASK, and 88% of clinics reported using the tools provided in the ASK. Only 12% reported never using it in their study activities.

While the prevention of adherence problems is recognized as a key issue, adherence and retention have historically been given fullest attention only after recruitment goals have been met. However, it is essential to be attentive to potential adherence issues during recruitment and screening, and to establish an adherence and retention protocol at the onset of a trial. The exclusion of a patient because of potential threats to adherence will better serve the adherence and retention goals of the study and its final power to answer the study question, a case of quality over quantity. Further, an initial focus on prevention of "lost" participants will alleviate the need to find or reinstate these study subjects later.

The experience of having a standardized approach to adherence practices is strongly recommended for other trials, specifically those trials in private practice clinics. The demands of business in private practice settings require an adherence program that is easy and acceptable, since ease of implementation and acceptance by clinical staff is crucial.


The Adherence Survival Kit was an organized approach to the management of retention and adherence issues in a large, long-term clinical trial. It was developed primarily for research-nave clinics, in response to the staff turnover experienced by many of the ALLHAT clinics. The ASK was well received by the ALLHAT clinics and was regarded as an effective tool for use in maintaining study participants on the protocol. Because adherence to study visits and medication is difficult to regain, an adherence protocol should be started early in any trial. An adherence guidebook and ASK-like tools can direct clinics to focus on retention and adherence details during all phases of a large simple trial.


1. J.L. Probstfield, M.L. Russel, W. Insull, S. Yusuf, "Dropouts from a Clinical Trial, Their Recovery and Characterization: A Basis for Dropout Management and Prevention," in 

 S. Shumaker, J. Ockene, and E. Schron, eds. (New York: Springer Publishing Co., 1990, pp. 376-400).

2. C.E. Davis, "Prerandomization Compliance Screening: A Statistician's View," in 

 S. Shumaker, J. Ockene, and E. Schron, eds. (New York: Springer Publishing Co., 1990, pp. 342-347).

3. B.R. Davis, J.A. Cutler, D.J. Gordon, et al. for the ALLHAT Research Group, "Rationale and Design for the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)," 

4. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, "Major Cardiovascular Events in Hypertensive Patients Randomized to Doxazosin vs. Chlorthalidone," 

Journal of the American Medical Association,

5. J.T. Wright, W.C. Cushman, B.R. Davis, et al. for the ALLHAT Research Group, "The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT); Clinical Center Recruitment Experience," 

6. L.M. Friedman, C.D. Furbert, D.L. DeMets, 

 3rd Ed. (St. Louis, MO: Mosby-Year Book, 1996).

7. L. Gorkin, M. Goldstein, M. Follick, R. Lefebvre, "Strategies for Enhancing Adherence in Clinical Trials," in 

 S. Shumaker, J. Ockene, and E. Schron, eds. (New York: Springer Publishing Co., 1990, pp. 361-375).

8. W.B. Applegate, "Follow-up and Adherence in Clinical Trials of Elderly Subjects," in Inclusion of Elderly Individuals in Clinical Trials: Cardiovascular Disease and Cardiovascular Therapy as a Model, N.K. Wenger, ed. (Marion Merrel Dow Inc., 1993, pp. 91-93). 

9. J.D. Neaton, R.H. Grimm, R.J. Prineas, et al., "Treatment of Mild Hypertension Study: Final Results," 

10. The Treatment of Mild Hypertension Research Group, "The Treatment of Mild Hypertension Study. A Randomized, Placebo-Controlled Trial of Nutritional-Hygienic Regimen Along with Various Drug Monotherapies," 

11. J.T. Wright, "ALLHAT Study: A Trial Long Overdue," 


This study is supported by contract with the National Heart, Lung and Blood Institute (NHLBI). The ALLHAT investigators acknowledge contributions of study medications supplied by Pfizer, Inc. (amlodipine and doxazosin), AstraZeneca (atenolol and lisinopril), and Bristol-Myers Squibb (pravastatin), and financial support provided by Pfizer to the NHLBI.

For a list of Project Office staff, DSMB, Steering Committee, Clinical Trials Center, regional teams, support centers, study centers and staff, and other acknowledgements, see JAMA, 283, 1967-1975 (2000).

PhD, are with The University of Texas Health Science Center School of Public Health, Houston, TX, (713) 500-9520, fax (713) 500-9530, email: spressel@sph.uth.tmc.edu.

BA, are with the Albert Einstein College of Medicine Bronx, New York, NY.

DrPH, are with the National Heart, Lung, and Blood Institute, Bethesda, MD.

 MD are with the University of Washington Medical Center, Seattle.

*To whom all correspondence should be addressed.

The Adherence Survival Kit

Paper-free clinical trials may not ever happen-but many of its advantages are already available.

We are nowhere near the nirvana of a completely paperless office. Yet the value of word processing, spreadsheets, and email is simply indisputable. Similarly, the vision of a completely paperless clinical trial from concept to submission is still on the distant horizon. Nevertheless, the industry has begun the steady elimination of paper in the management of clinical data and documents, from patient diaries to eCRFs to fully electronic submissions, and is reaping significant benefits. To understand this, let's look at the paperless office.

Office automation began taking the world by storm back in the days of the electric typewriter, made by IBM. The office progressed rapidly in the adoption of technology from the office copier (invented 1938, first practical commercial version 1959, both by Xerox), the fax machine (invented 1843(!), first practical commercial version 1966 by Xerox), to the dedicated word processing machine (invented in 1964, first practical commercial version 1969, both by IBM). A watershed event was the introduction of the IBM personal computer in 1981 with its "killer application." Many think that this "killer app" was the word processor, but actually it was considered to be the spreadsheet, invented by Dan Bricklin (a wonderful description of this can be found by visiting http://www.bricklin.com/history/saiidea.htm).

In these early days, many predicted the demise of paper in the office. The noted futurist Alvin Toffler said in 1970 that "making paper copies of anything is a primitive use of machines and violates their human spirit." The vision was of a paperless office, where all documents are outlined, created, reviewed, communicated, commented upon, and read online. There would be no reason, so we were told, to ever print paper. This future would be bright, cheerful, and efficient. Nobody would ever have to search for a document, as they would all be available at one's voice command. Viewed more than 30 years later, this vision is almost laughable.

The facts are even more shocking. The use of paper in offices, from the printing of  emails and Web pages, is growing at 6-8% per year, with the average employee printing 33 Internet pages per day. Paper usage doubled from 1981 (the introduction of the PC) to 1995, and most people feel swamped with paper in many forms. We still print out our documents to read and review, keep paper to-do lists, and get our industry news in printed magazines.

Don't misunderstand my point here-the digital revolution has changed the world in profound and mostly positive ways. And newer add-on technologies continue to add organizational and efficiency benefits. For example, OnFolio is a product that integrates with your Web browser and allows you to "file" Web pages, emails, Word documents, PDFs, and other documents in tidy folders available at a moment's notice.

But the paperless office is simply a myth today, and will remain so for the remainder of our lifetime. And this isn't a bad thing. Why is paper so stubbornly resistant to extinction? First of all, paper is just a wonderful thing to use. It is easy on the eyes, nice to hold, carry, and about as portable as an information technology can be. It is relatively inexpensive and reasonably well made-paper can last centuries. Aside from writing on the paper, there is a world of additional information that can be obtained from it-the quality of the paper, whether it is wrinkled or not, even the presence of coffee stains. Paper is comfortable for us to read, wherever we go.

Applied Clinical Trials-10-01-2004

Retaining Subjects Is Harder Than Recruiting Them

New Guidances Try to Keep Up with Progress

The Quality Coach

Handbook of SOPs for Good Clinical Practice, Second edition

eShowcase

The Adherence Survival Kit

The Fully Electronic Office (or Clinical Trial) Myth

Going The Distance

Clinical Trial Listings and Results Go Public

A Closer Look at the 1572: Interpreting the FDA's Statement of Investigator Form