The European Union is constantly in a legislative fervor, as this column has repeatedly demonstrated. In trying to create common pharmaceutical rules (and rules on many other areas of life and work) for 15 countriesand ensure implementation of them and compliance with themit inevitably devotes much of its energy to what is essentially police work. And with another 10 countries likely to join the EU in just over two years, the making and enforcing of rules will become even more complicated and time-consuming. 

But policing is not the EUs only role in the medical and pharmaceutical arena. The EU also spends money, time, and energy backing research. This column has recently reported on the planning for the E17 billion EU research program for 20022006planning that has almost reached a conclusion in the EUs own labyrinthine system, and will pump billions of euros into clinical research over the next four years. So before that plan is finalized (and before the EU gets bogged down in another round of legislation to cope with the new eastern European and Mediterranean member states it is taking on board), perhaps it is time to look at some of what the EU has done in its role as research supporter rather than as medicines regulator. And because cancer has been repeatedly recognized as one of Europes biggest killersit is a key priority in the EUs new research programit seems apt to take the EU action on cancer as an index of how effective it is as physician rather than police officer. More than E1 billion is currently earmarked for fighting major diseases under the upcoming program, of which E400 million should go towards cancer research.


The most recent example of what has been done dates from just a few weeks agothe announcement of the latest results from EU-backed trials on isotopes in the fight against cancer. Preliminary clinical trials carried out by researchers at the European Commissions Joint Research Centre in Karlsruhe, Germany, and the German Cancer Research Centre in Heidelberg show that alpha-emitting radioisotopes can kill cancer cells, offering new hope of combating cancers such as leukemia, ovarian cancer, and skin cancer. The cancer-killing mechanism works by connecting a vehicle that targets cancer cells, such as a monoclonal antibody or a peptide, to a powerful radioactive isotope. As it decays, the isotope emits particles that kill any cancer cells the vehicle encounters. In announcing the results, the Commission said the findings show that alpha-immunotherapy has the potential to develop into an effective treatment over the next few years and may lead to new methods of healing patients. 

The work was funded with a E1.4 million contribution from the European Commission, under a project on the treatment of non-Hodgkins lymphoma, which began in January 1999 and ended in June 2002. More research is needed, but experts tell us that the results from preclinical and first clinical trials are promising, said European Research Commissioner Philippe Busquin. Multi-disciplinary cooperation between Europes best teams is needed to advance this innovative approach. 

And in reviewing its support for cancer research earlier this summer in an article in 

 an online magazine about European research,1 the Commission congratulated itself on its contribution: after decades of research, it found progress at every levelprevention, detection, and treatmentmeaning that nearly one in two cancer patients is still alive five years after the initial diagnosis.  For many pathological forms, cancer should no longer be seen as an inevitably fatal disease but as a chronic and potentially reversible one, said Shahid Baig, director of EU research programs for cancer. 

Nonetheless, every year nearly four million new cancer cases are diagnosed in Europe, and with 750,000 deaths a year it is the second cause of mortality among the EU population. Although this high mortality rate is partly linked to the aging population, one in three Europeans is hit by cancer before the age of 75. 


The Commissions approach to cancer research takes account of the complexity and diversity of the disease. There are over 200 types of cancer, all with their own metabolic particularities about which we sometimes understand very little, the Commission points out in the 

 article. The fight against cancer therefore requires a multi-pronged approach. The essence of the EU action is therefore to integrate research activities to create a synergy effect between the work of national governments throughout Europe and the pharmaceutical industry. So it has supported Europe-wide epidemiological studies to obtain a global view as a basis for developing and validating increasingly early and reliable methods of diagnosis. And it has supported various transnational networks set up in the fight against cancer. These guarantee the reliability and safety of scientific advances and enable all practitioners to benefit from the progress made and know-how acquired, it claims.

In addition it has focused on integration between fundamental research and clinical research, and between oncology, genetics, biochemistry, biophysics, surgery, and other disciplines involved in developing new treatments. The barriers between these disciplines must continue to be eroded, it says. The development of translational research is valuable in this respect, promoting an interdisciplinary approach and the flow of information between fundamental researchers and clinical practitioners. This rapid move from fundamental research to clinical applications has become a priority, not only because it is the patients right to have access to scientific progress but also because, in a highly competitive international environment, a heavy price is paid for any delay. And the Commission stresses the need for research to take into account patients quality of life.

The rationale behind the Commissions efforts at integration is that no single country can work in isolation and that compared with the United States, for example, where research by the National Institutes of Health is integrated nationally, European cancer research too often suffers from a duplication of research efforts.

 Lauri Aaltonen of Helsinki University is currently coordinating research by several European teams on Peutz-Jeghers syndrome (PJS), and has identified the LKB1 gene which mutates to cause PJS. LKB1 and the protein whose synthesis it controls evidently play a key role in the appearance of a whole family of very different cancers (intestine, breast, uterus, etc.), explains Aaltonen. Sharing the same interest in the fundamental mechanisms of cancer, Jean-Marie Blanchard of the Institut de Gntique Molculaire de Montpellier in France and his team are working with EU support on assessing cancer as a cellular signaling disease. We have studied the action of a particular molecule in cellular signaling, TGFb, explains Blanchard. Cancer cells manage to escape the action of TGFb. Once we have understood how, we can seek ways of correcting this malfunctioning.

A number of European laboratoriesin particular those working on the EU-backed inducible melanoma model projectare trying to develop transgenic mice expressing human tumors to study their characteristics. Medical imaging is also benefiting from research on breast cancer carried out by five European laboratories with EU support. We have developed a method of surgery guided by magnetic resonance imaging, according to project coordinator Sylvia Heywang-Kobriunner of Halle University in Germany. This method offers many benefits: less damage is done to the breast, there are cleaner margins around the tumor, and the risk of residual tumors is avoided. In January, a team from the European Molecular Biology Laboratory in Heidelberg, Germany, headed by Giulio Superti-Furga, announced the discovery of a molecular mechanism which is the cause of several types of lethal leukemias. 

 And a sizable wedge of EU money goes into supporting the European Organisation for Research and Treatment of Cancer (EORTC). With 2500 voluntary practitioners in some 200 hospitals, it is described by the European Commission as a major spearhead in the global fight against cancer . . . By organizing rigorous clinical trials on a vast scale it has permitted major progress in the treatment of the most varied forms of the disease. As Franoise Meunier, the organizations director general, was quoted in the 

 article, At first it was no more than a meeting of a select group of eminent and visionary oncologists without any mandate. But given the urgency of the fight against cancer they were aware that one country alone would never be able to cope and that it was crucial to make the most of the potential offered by European coordination of clinical research.


Nevertheless, despite all its activities in direct support of treatment, policing remains the European Unions principal role. Among the latest examples of this are two further draft guidelines which have appeared as the continuing follow-up to the 2001 clinical trials rules in the EU (pharmacos.eudra.org/F2/ pharmacos/docs/Doc2002/june/ ins_gcp_06_2002. pdf). One relates to the qualifications of inspectors who are to verify compliance in clinical trials with the provisions of good clinical practice for an investigational medicinal product. The other concerns inspection procedures themselves for the verification of GCP compliance.

The guideline on inspectors demonstrates one of the curious aspects of the EU acting as a police officer: it will obtain a successful result indirectly rather than directly. The guideline requires member states to appoint inspectors to inspect the sites concerned by any clinical trial conducted, and with sufficient resources at all levels to meet, effectively and efficiently, the requirements of verifying compliance with GCP and GMP of investigational medicinal products used in clinical trials. The inspectors are to be officials of the national authorities, or appointed by them, and competent to carry out their assigned duties. They also have to receive appropriate training, and each member state has to act to maintain and improve inspection skills. Inspectors necessary qualifications include high personal integrity, maturity, be open-minded, understanding of complexity, possess sound judgment, assertiveness, analytical skills and tenacity and have the ability to perceive situations in a realistic way.

In fact, the minimum requirements set out hardly seem arduous:
The inspector should preferably have completed education at university level, or equivalent, in medicine, pharmacy, pharmacology, toxicology or other relevant fields. The level of education should allow good communication with all persons concerned with the clinical trial from sponsor, investigator or ethics committee. The inspector should have demonstrated competence in clearly and fluently expressing concepts and ideas orally and in writing in their officially recognized language. The inspector should have knowledge of the principles for development of drugs and clinical research procedures as well as requirements for clinical trials. This includes knowing the role of pharmaceutical, preclinical and clinical documentation. The inspector should have knowledge of the national legislation as well as systems, national and within EU, for conducting clinical trials and applications for marketing and control of marketed drugs. Basic medical terminology should be known and the inspector should be familiar with medical procedures and systems for recording clinical data, as well as member state regulations for the work and procedures of health care personnel and organizations providing care to patients. When applicable the inspector should also understand the patient care and regulatory systems of other countries. To be able to act as lead inspector [in EU-level inspections] and to participate in the ongoing cooperation and harmonization of procedures within EU, the inspector should also be able to write and speak English.

The relatively low level of requirements does not, however, suggest that the EU is not able to discharge its role as a police officer. The guidelines set out minimum requirements for inspectors on education, training, independence, seniority, and so on, and none of them are anything more than would have been expected for such a job. The fact that the minimum qualifications are not explicitly high is not surprising, because they result from a European-level process. Each member state will have to provide inspectors for clinical trials from its nationally available pool of talent. For large countries such as the UK or Germany, this presents no problem. For smaller countriesand plenty of EU member states have only a few million citizens (Luxembourg has only 300,000)the problem is more acute. 

Because guidelines of this sort have to be agreed upon by all member states, the explicit barriers are not set impossibly high. To have insisted on a more rigorous list of minimum requirements would have run into difficultiessome member states might not have been able to back them. That would not have raised the standards of inspection, and would have held up the installation of a slightly more standardized European system. What counts, however, is the implementationand because (for instance) few clinical trials are conducted in Luxembourg, it will need few inspectors, while in the United Kingdom, where many are conducted, it will be possible to find plenty of adequate inspectors. The real arbiter will be peer pressure in practicewhich will ensure that where inspectors are nominated and active, they operate at levels judged acceptable across Europe. In true European style, this will emerge from pragmatic experience, rather than from a list of minimum academic requirements. 

 April 2002, europa.eu.int/ comm/research/news-centre/en/ med/02-03-med01.html.            

Articles

View from Brussels

The EU?s progress in the battle against cancer measures how effective it is as research supporter instead of regulatory enforcer.

EU as Physician Rather than Police Officer

Modern imaging technologies are being used with increasing frequency during evaluation of oncology drugs in clinical trials. Cross-sectional radiological imaging, particularly computed tomography and magnetic resonance imaging, has established a central role in the management of cancer patients.

 Because imaging is very reliable for detection and characterization of cancers, it can serve to guide therapy by noninvasively monitoring treatment response. 

Drug-regulating agencies such as the Food and Drug Administration (FDA) are willing to provide expedited approval of cancer drugs developed for treatment of cancers for which no adequate alternative is available.

 Because imaging can provide objective evidence of tumor shrinkage, it can help rapidly establish drug efficacy by supplementing subjective clinical endpoints such as quality of life. For example, FDA approved the anti-cancer drug capecitabine following an image-based oncology trial comprising only 162 subjects.

This article identifies the critical success factors that allow effective use of radiology in the clinical evaluation of oncology drugs.


Recent and ongoing technological advances in imaging technology and diagnostic contrast media have revolutionized the role of radiology in clinical practice. The technical advances include not only faster volumetric imaging (multislice computed tomography, or CT, and 3D magnetic resonance imaging, or MRI), but also functional imaging (positron emission tomography, or PET). Very accurate noninvasive monitoring of tumor burden is made possible by the ability to obtain high-quality, thin-slice, modern-day CT and MRI images in a single breath-hold using newer tissue-specific contrast media followed by superior image processing.

 Radiologists can now evaluate tumor size with a high degree of precision, and can readily obtain tumor volumes. They can accurately quantify treatment response by comparing pretreatment and posttreatment measurements of tumor burden.

Radiological methods may not be appropriate, however, in certain cancers. For example, imaging has a very limited role in patients with leukemia and other hematological malignancies. Blood tests and other lab investigations may be more appropriate in such contexts. Thus oncologists need to continually evaluate the potential role of radiology in determining tumor burden, including determining which imaging method would be best used to estimate tumor burden in light of the rapid evolution of imaging technology.

A bewildering array of imaging modalities are available for potential use in drug trials. Plain radiography, sonography, CT, MRI, and radionuclide studies are now widely available. Recent advances in CT, MRI, and PET have completely revolutionized imaging, opening up many potential applications.

 Faster imaging, thinner slice-profile, better 3-D reconstruction, and perfusion mapping are some of the advantages of the current helical CT technology.

 Advances in MR technology such as spectroscopy, perfusion imaging, and diffusion imaging provide important physiological and biochemical data in addition to the anatomical information.

It is now possible to image changes in tumor perfusion and metabolism and hence better evaluate treatment response before a change in tumor size takes place. Diffusion MRI, MR spectroscopy, perfusion CT and MRI, and molecular imaging detect changes in tumor perfusion and metabolism earlier than the conventional radiological techniques.

 The principal investigator should select the appropriate imaging modality to be used before initiation of the study.For example, whereas tumor size surveillance is appropriate in evaluating the efficacy of cytotoxic drugs, perfusion studies may be ideally suited for evaluating tumors treated with anti-angiogenesis drugs.

 The efficacy of tumor vaccines and gene-based drugs is best analyzed by molecular imaging strategies.

 The radiologists input in this context is invaluable.

A wide variation exists in the type of scanners, scanning parameters, and scanning techniques used, providing varying results. For example, radiology literature documents that imaging of the liver during the equilibrium phase may result in suboptimal visualization of lesions.

Variation in imaging practices is a major disadvantage of multicenter clinical trials, potentially giving rise to confounding results. In a multicenter drug trial, it is imperative to choose sites that can support optimal and uniform imaging techniques. The adoption of a standard set of diagnostic imaging guidelines improves the value of imaging when used to measure tumor burden.


The use of Internet-based technologies in clinical trials has increased dramatically in a number of areas: electronic capture and transmission of clinical trials data; recruitment process by all trial participants, including subjects and investigators; and filing of new drug approval applications with government regulatory agencies.

By taking advantage of the network architecture that exists for the Internet, many trials can benefit from image transfer methods and Internet topology already in place.The future standard of managing medical imaging is envisioned as a combination of several key technological components and processes in a well-designed image file transfer architecture. This architecture, through the extensive use of the Internet, will significantly address the traditional problem areas of applied clinical trials. Most important in trials is the collaboration of the equipment vendors, the pharmaceutical companies, and the image management companies to provide a technical solution that is cost-effective, technologically robust, and globally accessible. 

With rapid developments in the field of telemedicine and picture archival and communication systems (PACS), many radiology departments are increasingly becoming filmless.

 The advantages of reading directly from the monitor are numerous and include the ability to change the image characteristics by altering window settings, easy image transfer, and the ability to superimpose different imaging modalities of different data content. These abilities enhance the performance of the radiologist. Other advantages include accurate measurement using digital calipers, use of digital overlays, and the potential use of automated analysis by sophisticated image-analysis software tools.

In addition, considerable time savings can be achieved through secure transmission of digital images via the Internet. Electronic transfer of data is also more economical than shipping hard copies. 

Conventionally, clinical investigators at the clinical site where subjects were imaged (that is, on-site) typically interpreted the images. Both drug regulatory agencies and pharmaceutical companies now often opt for independent evaluation of the images by a select group of expert physicians (off-site) who are blinded to the clinical data. This practice potentially reduces bias and interobserver variation in data analysis.

Involving subspecialty-trained radiologists in image interpretation is equally critical for optimal results. Precise tumor characterization and accurate tumor delineation are crucial factors in interpreting images. For example, surveillance of subjects with brain tumors is best served by neuroradiologists who have considerable experience and expertise in interpreting brain MRIs. On the other hand, gastrointestinal radiologists are better suited to interpret the CT images of subjects with colon cancer.

In addition, regulatory agencies mandate unbiased evaluation of images at randomized visits that are best done in off-site locations. Several studies indicate that off-site evaluation of studies improves consistency, reliability, accuracy, and reproducibility of readings.

 As a result, the image analyses in image-based oncology drug trials are increasingly performed in off-site core laboratories. 


Serial evaluation of tumor size following treatment provides objective evidence of drug efficacy. For more than two decades, the World Health Organization (WHO) criteria for categorizing patient response were used.

 The WHO (bidimensional) technique consists of measuring each tumor twicetwo mutually perpendicular diametersand obtaining the product, or cross-product, of these diameters. The cross-products are then compared to categorize patient response.

Advances in imaging technology largely prompted an international working group to set new guidelines to evaluate patient response. The new recommendations, referred to as response evaluation criteria in solid tumors, or RECIST, simplified the measurement technique and advocated the use of unidimensional measurements.

 The differences in the two techniques are summarized in Table 1.

Since most tumors are spherical, criteria based on diameter, cross-sectional area, and volume are interchangeable.

 In a subset of tumors with asymmetrical tumor shrinkage or growth or non-ellipsoidal morphology, discrepancies between the two techniques are likely to set in. With advances in imaging technology that permit tumoral volumetric computations, criteria based on volume may be expected.


Investigators should continually review and update the methods used in data analysis, if needed. Continual review permits early detection of flaws in the methods and the opportunity to take corrective steps. Keeping the evaluation criteria as objective as possible can reduce interobserver variation.


Modern-day radiologic imaging can provide highly accurate, reproducible measures of viable tumor burden. Subspecialty radiologist analysis in an electronic environment provides a very thorough image analysis and a faster and more cost-effective means of evaluating drug efficacy. 

1. M. Hasegawa, S. Sone, and S. Takashima, et al., Growth Rate of Small Lung Cancers Detected on Mass CT Screening, 

2. L.E. Hann, C.B. Winston, K.T. Brown, and T. Akhurst, Diagnostic Imaging Approaches and Relationship to Hepatobiliary Cancer Staging and Therapy, 

3. Food and Drug Administration, Guidance for Industry, FDA Approval of New Cancer Treatment Uses for Marketed Drug and Biological Products (U.S. Department of Health and Human Services, FDA Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, December 1998, Clin 7). 

4. J.L. Blum, S.E. Jones, and A.U. Buzdar, et al., Multicenter Phase II Study of Capecitabine in Paclitaxel-Refractory Metastatic Breast Cancer, 

5. K. Klingenbeck-Regn, S. Schaller, T. Flohr, B. Ohnesorge, A.F. Kopp, and U. Baum, Subsecond Multi-slice Computed Tomography: Basics and Applications, 

6. H. Hu, H.D. He, W.D. Foley, and S.H. Fox, Four Multidetector-row Helical CT: Image Quality and Volume Coverage Speed, 

7. M. Poustchi-Amin and J.J. Brown, Echo-planar MRI Allows Study of Fast-changing Physiologic Processes, 

8. J.P. Earls and D.A. Bluemke, New MR Imaging Contrast Agents, 

Magnetic Resonance Imaging Clinics of North America, 

9. U. Roelcke and K.L. Leenders, Positron Emission Tomography in Patients with Primary CNS Lymphomas, 

10. J.C. Wong, J.M. Provenzale, and J.R. Petrella, Perfusion MR Imaging of Brain Neoplasms, 

11. R. Brasch and K. Turetschek, MRI Characterization of Tumors and Grading Angiogenesis Using Macromolecular Contrast Media: Status Report, 

12. T.L. Chenevert, L.D. Stegman, and J.M. Taylor, et al., Diffusion Magnetic Resonance Imaging: An Early Surrogate Marker of Therapeutic Efficacy in Brain Tumors, 

13. C. Harvey, A. Dooher, J. Morgan, M. Blomley, and P. Dawson, Imaging of Tumour Therapy Responses by Dynamic CT, 

14. J.M. Cherrington, L.M. Strawn, and L.K. Shawver, New Paradigms for the Treatment of Cancer: The Role of Anti-Angiogenesis Agents, 

15. T. Mikkelsen, Cytostatic Agents in the Management of Malignant Gliomas, 

16. J.L. Blum, Xeloda in the Treatment of Metastatic Breast Cancer, 

17. C. Bremer and R. Weissleder, In Vivo Imaging of Gene Expression, 

18. P. Wunderbaldinger, A. Bogdanov, and R. Weissleder, New Approaches for Imaging in Gene Therapy, 

19. P. Dawson and J. Morgan, The Meaning and Significance of the Equilibrium Phase in Enhanced Computed Tomography of the Liver, 

20. R.L. Arenson, K.P. Andriole, D.E. Avrin, and R.G. Gould, Computers in Imaging and Health Care: Now and in the Future, 

21. L.H. Schwartz, M.S. Ginsberg, and D. DeCorato, et al., Evaluation of Tumor Measurements in Oncology: Use of Film-based and Electronic Techniques, 

22. D. Sahani, S. Saini, and G.A. Fatuga, et al., Quantitative Measurements of Medical Images for Pharmaceutical Clinical Trials: Comparison between On-site and Off-site Assessments, 

23. A.B. Miller, B. Hoogstraten, M. Staquet, and A. Winkler, Reporting Results of Cancer Treatment, 

24. P. Therasse, S.G. Arbuk, and E.A. Eisenhauer, et al., New Guidelines to Evaluate Response to Treatment in Solid Tumors, 

25. S. Saini, Radiologic Measurement of Tumor Size in Clinical Trials: Past, Present, and Future, 

Feature Article

Modern radiological techniques and digital analysis technologies permit rapid evaluation of the efficacy of oncology drugs. Continual review of methods detects flaws promptly, creating the opportunity to take corrective steps.

Radiology in Oncology Trials: Critical Success Factors

A set of trials carried out by the Collaborative Ocular Melanoma Study Group at eye centers throughout the United States and Canada led to improvements in the care of patients with choroidal melanoma.

Changing Current Practice

Subject diaries are used in approximately 25% of all  clinical trials.

 They have been developed using one of three types of diary technologies. The traditional approach has been to use paper cards or booklets configured to help the subject follow directions from the clinical protocol. More recently, electronic means have been used, such as dial-in phone numbers with computer-driven questions to answer (interactive voice response systems) and handheld devices with alarms and menu-driven prompts to guide the subject through the protocol requirements.

Subject diaries are used to directly capture subjects experiences surrounding a medical momentthe subject experience prescribed for capture by the clinical protocol whether it is physical or time/logic-based experience. Medical moments may include symptom counts (for example, involuntary micturitions, migraine episodes), subjective symptoms (for example, discomfort surrounding an involuntary micturition, pain severity of a migraine), and quality of life (for example, activity restrictions due to involuntary micturitions or migraines).

 Subjects record this information as they go through day-to-day life. The goal is that when the appropriate medical moment occurs, the subject makes an appropriate recording into the diary. Because the diary is the subjects first record of an experience, it is source data. This differentiates diary data from case report form (CRF) data, which are copied from many other sources in the subjects medical file.

Given the importance of subject diaries in clinical research, this article, the first in a series, discusses the relevant regulations and guidance that must be followed to obtain the high standards of data quality set by regulatory bodies. This series is intended to extend previous articles published by Applied Clinical Trials that compare and contrast diary methods

 The two authors will approach the subject from different backgrounds. Teri Stokes, a global validation consultant, will take a technology/regulatory perspective. Jean Paty, a clinical researcher, will take a scientific/regulatory perspective. Both authors prefer electronic solutions; however, both traditional paper and electronic approaches for subject diaries will be discussed. 

The basic concern of regulators is data integrity and data quality regardless of the method used to acquire it. This first article discusses regulators focus on ensuring that they can have confidence in the data. Future articles in this series will explore designing clinical protocols for diary data quality, system and clinical challenges for validation of electronic diaries, and standard practices and issues arising from practical experience with electronic diaries. Each article will pose four relevant questions, with the two authors responses presented for comparison. 

In this article, the authors address the following questions about regulatory issues in subject diary research:

	Why are subject diaries important to clinical research?

	How does ICH GCP apply to subject diarieselectronic and paper?

	How do FDA guidance and 21 CFR 11 apply to subject diarieselectronic and paper?

	What are the audit and inspection criteria for subject diary data?

Stokes, as the validation expert, will address those parts of the regulations that place direct demands on the design and development of a diary system. Patys background in clinical research will focus his discussion on those parts of the regulations that most directly affect study design and methodological rigor for using diaries.

Why are subject diaries important to clinical research?

Technical  systems/regulatory perspective, Teri Stokes:

 The investigator has limited time with a subject to make observations and assessments of how well a study treatment is working for a particular subject. Capturing the subjects personal experience in a diary at set times between office visits can add much important information about the safety and efficacy of a treatment. Whatever the diary technology (paper, handheld device, or IVRS), the subject is the one person best able to record self-reports at prescribed time intervals.

Clinical science/regulatory perspective, Jean Paty:

 Understanding the subjects perspective, in addition to physiological effects, is critical in evaluating the safety and efficacy of a drug. Indeed, in a number of therapeutic categories (for example, incontinence and migraines), the subjects self-report is the primary endpoint for evaluating the efficacy of the drug. When the subjects self-report, via a diary, is not the primary endpoint, it is often a key secondary endpoint in determining drug efficacy; for example, subjects reports of day- and nighttime asthmatic symptoms are key secondary parameters in evaluating respiratory drugs. Finally, quality of life data will play a central role in drug development, because subjects want not only to be labeled better by some objective medical standard, but to feel better as well. 

 Accurate and timely subject diaries are important because they provide a unique inside-the-subject view of what is happening in a clinical trial. While all diaries provide self-assessment data, electronic diary methods also provide audit trail records that show how well subjects comply with the protocol for recording self-assessments. Electronic systems can remind subjects about important events in a complex treatment regimen, and they can prevent  out-of-sequence assessments. Between-visit uploads from electronic diaries can provide the investigator with quicker access to diary data so that medical care can be more responsive to subject needs. 

 In practice, it is not simple to get subjects to reliably complete their diaries in the context of daily life. Unlike research staff, subjects are not accustomed to completing research questions. Moreover, diaries require subjects to take time out of their day-to-day activities to make entries about disease events that might be quite unpleasant for them (for example, migraines). Finally, the information captured from the subject must meet scientific and regulatory standards for rigor, reliability, and accuracy. Thus, there are a number of factors to balance when developing and implementing a subject diary. These issues have led to the development of electronic diaries, which can yield very high rates of compliance from subjects and meet scientific and regulatory requirements.      

How does ICH GCP apply to subject diarieselectronic and paper?

 The International Conference on Harmonization (ICH) developed a Guideline on Good Clinical Practice (GCP) to provide a unified standard for the European Union (EU), Japan, and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions. In section 1.52 of the ICH GCP, the definition of Source Documents gives as a specific example subjects diaries or evaluation checklists.

 This classifies both paper and electronic diaries as source documents, and as per section 8.3.13, subject diaries are to be protected and archived with the trial file at the investigator site. For a more detailed treatment, the reader is referred to an ongoing discussion in Applied Clinical Trials regarding reg-ulatory issues surrounding electronic source documents. The most recent installment is from Paul Bleicher in August 2002.

 The ICH GCP Guideline (section 2.10) makes the following statement regarding data: All clinical information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification. The ICH GCP also requires that the investigator should ensure the accuracy, completeness, legibility, and timeliness of the data reported to the sponsor in the CRFs and all required reports. (Section 4.9.1).      

 Being a source document differentiates the subjects diary from the subjects case report form (CRF), which is a collection of data derived from many source documents in a subjects medical file. The investigator is responsible for retaining all original source documents whereas the sponsor is responsible for keeping the original of the CRFs.  

 Historically, diaries have taken the form of paper booklets or cards given to subjects at study visits, and completed by the subject each day, during the course of everyday life. A number of studies, including a recent one published in the British Medical Journal,

 have shown that subjects do not complete these paper diaries in a timely manner. In that study subjects entered only 11% of their diary entries in compliance with study procedures. This raises the question of the accuracy of subject reports with traditional paper diaries. Electronic diaries have been shown to yield high rates of compliance with timely completion.      

 Paper diaries always go to the investigator first. When electronic diaries are used, they are often developed and deployed by a third-party service provider on behalf of the sponsor. It is important for sponsor and suppliers to remember that the diary data is source data and belongs with the investigator under ICH GCP. During the trial, the investigator must have immediate online access to diary data so that the medical moment(s) described therein can be incorporated into the subjects medical care. At the end of the trial, a certified copy of all the subjects diary data must be sent to the investigator for retention with the investigators trial source records to support future audits and inspections.   

 Published research using electronic diaries provides evidence that this approach can yield data of high quality and integrity (see the recent review in the April 2002 issue of 

 One such study was conducted using electronic diaries with smokers trying to quit.

 The study required that subjects report their craving to smoke throughout the day. Traditionally, this would have been captured by asking the subjects to make a single entry at the end of the day about their smoking. However, by giving each of them a handheld computer, it was possible to ask subjects about their craving 8 to 10 times each day. Subjects recorded the relevant medical moment, in the moment, rather than later on. The results showed that subjects readily complied with these procedures, responding to over 90% of the handhelds prompts to answer questions about craving.

 Processing and access to electronic CRF data can and usually does occur long after the investigator has processed the medical moment (visit, assessment, test, episode) in a trial. Electronic diary data, however, is part of the medical moment itself and must reach the investigator for diagnostic processing in the shortest possible time, even though it may be first received on the server of a sponsor, service provider, or CRO.   

 Thus, electronic methods can yield high rates of subject compliance with protocol procedures and scientific rigor. This higher compliance will in turn yield more reliable and potentially more accurate data, which makes electronic diary methods compliant with ICH data quality guidelines.

 As per ICH GCP section 5.5.3 on electronic data handling, an electronic diary system has to be validated, have an SOP for its use, include an audit trail, and have security that prevents unauthorized use. Only authorized individuals should be allowed to make data changes on the system, the data must have adequate backup, and any blinding must be safeguarded. Finally, section 5.1.3 states, Quality control should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly.

How do FDA guidance and 21 CFR 11 apply to subject diarieselectronic and paper?

 The Food and Drug Administration passed a two-part law in 1997 in parallel to implementing the ICH GCP. The Final Rule on Electronic Records and Electronic Signatures (21 CFR 11) applies to electronic subject diaries as electronic records, and when electronic signatures are used, it applies to the signatures as well. This law does not apply to paper diaries unless they are scanned into electronic form and archived as electronic records. 

 Whether a paper or electronic diary is used, it must yield high data quality and integrity. The FDA makes the following statements in the April 1999 Guidance for Industry: Computerized Systems Used in Clinical Trials:
FDAs acceptance of data from clinical trials for decision-making purposes is dependent upon its ability to verify the quality and integrity of such data during onsite inspections and audits. To be acceptable the data should meet certain fundamental elements of quality whether collected or recorded electronically or on paper. Data should be attributable, original, accurate, contemporaneous, legible.

 These five components of data quality and integrity have been conveniently labeled ALCOA.      

 21 CFR 11 echoes all of the ICH GCP concerns mentioned above. It adds time-stamping to the audit trail so that local time can be established for any edits or changes and the use of operational system checks to enforce permitted sequencing of steps and events, as appropriate.

 These two new Part 11 components are very important for subject diaries and describe the key ways that an electronic diary performs better than a paper diary. A combination of alarms, prompts, and lockouts in the electronic diary can enforce protocol requirements for subject responses to be made in a specified sequence and at prescribed times.   

 Timely or contemporaneous recording of subjects experiences, or medical moments, is one of the key components of the ALCOA standard of data quality and integrity. If subjects wait to record the relevant information from a medical moment, be it a brief episode of urinary incontinence or an extended migraine headache, the impact of other life experiences will affect the accuracy of their recording. Again, the subject diary method employed must be shown to meet the ALCOA standards, whether it is paper or electronic.    

 Paper diaries can be filled in at any time, and this fact leads to the questionable accuracy of their data. Part 11compliant electronic diaries structure response times to the protocol design by allowing data entry only at specific times, time-stamping subject entries, and preventing subjects from entering data out of sequence.

Other Part 11 concepts include the use of device checks to determine the validity of source data input and the use of electronic signatures. Part 11compliant electronic diaries use handheld devices with unique identifiers and have software that can check the device ID communicated during a transmission. Such a check ensures that the device has been assigned to the subject, trial, and site identified in the diary report during each upload to the database server. With paper diaries, the subjects handwriting is unique, but if the subject forgets to sign the diary card and the report is mostly check boxes and analog graph lines, this could present an authentication problem.

The use of electronic signatures brings with it a technical burden described in sections 11.50 and 11.70 and an administrative burden as per Subpart C of Part 11. From a practical perspective, it is best to limit the use of electronic signatures in clinical trials to only those places where a handwritten signature is mandated. There is no legal mandate for a handwritten signature on subject diaries. One option to ensure authentication of the source for electronic diary data is the use of one password by the subject and the device checking performed by the server software.         

What are the audit and inspection criteria for subject diary data? 

 As an introduction to his paper on FDAs good laboratory practices (GLP) and computerized data acquisition systems in 1992, Paul D. Lepore of the FDA published a definition of what the FDA means by the terms data quality and data integrity. Lepore stated that the important characteristics of data quality are that the data are accurate, immediate, legible, durable, and attributable.

 He then stated that the important characteristics of data integrity are consistency, fidelity, and honesty.

 These criteria for data quality and integrity can be applied to diary data irrespective of the collection methodelectronic or paper. The Lepore paper on GLP data quality provides historical context for the ALCOA standard for GCP data on clinical trial systems in FDAs 1999 Guidance.  

 According to the Computerized Systems Used in Clinical Trials Guidance, inspectors will look to verify the quality and integrity of the data.

 From a practical perspective, this will mean evaluating the diary using the ALCOA standard. The challenges will be different for paper versus electronic diary methods, as shown in the table Technical/Regulatory Perspective on ALCOA.      

 Auditors and inspectors will seek to examine documented evidence of these characteristics when diary data are used to support endpoints in pivotal studies. Specific application of these characteristics to electronic diaries is given in the table.  

 From a clinical perspective, it is essential that the data reported on diaries be clear and usable for the investigator as a start, and then later for the CRA and sponsor. With paper diaries, legibility and completeness are consistent problems. If the diary is not legible, it is functionally incomplete. This missing information creates gaps that the investigator cannot fill at the site weeks, or even months, after the fact. This is, of course, problematic if the investigator needs to use this information during the course of the trial to make a medical decision.

 Every audit and inspection has training records on its checklist, and Part 11 section 11.10 (i) requires that persons who develop, maintain, or use electronic record/electronic signature systems have the education, training, and experience to perform their assigned tasks.

 It is important to have training materials and training records for both investigator staff and subjects using electronic diaries. If there are no instructions and/or users have not been trained in how to complete a diary record in either paper or electronic form, then the quality and validity of the data may be compromised.  

 Problems with legibility and completeness directly affect data quality and the ability to use the data to evaluate the primary and secondary aims of the study. If the CRA and data management group at the sponsor cannot read the data, then it will be very difficult to capture it in a database. In turn, analysis of the data becomes difficult. The scientific importance of high data qualitythat diary data be clear, legible, and completecannot be overemphasized.       

 In addition, it is important that the diary provider(s) have training records for their software developers and the personnel who configure and manage the trial diary process for a specific study. For paper diaries, only instruction materials and training for investigator staff and subjects are needed, but training records should still be kept.         


In this discussion, two perspectivestechnical systems and clinical scienceconverge on a common message: Subject diaries are important to trials where the clinical protocol uses self-reports as primary or secondary endpoints, and the quality and integrity of subject diary data is essential to the credibility of such trials. Regulations, guidance, and published papers state requirements for data quality and data integrity that apply to both paper and electronic diary systems. This discussion suggests that electronic diaries can potentially comply with ALCOA standards of quality and integrity more readily than paper diaries. FDA Guidance and other regulations (21 CFR 11 and ICH GCP) do provide useful guidance to support development of compliant electronic diary systems. The next article in this series (Part 2) will discuss how clinical protocol design and electronic diary design must work together to achieve data quality and regulatory compliance.

1. DataEdge, 1999. Unpublished data regarding frequency of use of diaries in clinical trials.
2. Saul Shiffman, Michael Hufford, and Jean Paty, Subject Experience Diaries in Clinical Research, Part 1: The Subject Experience Movement. 

 February 2001, 4656.
3. Stephen Raymond and Robert Ross, Electronic Subject Diaries in Clinical Trials, 

 March 2000, 4858. 
4. Michael Hufford and Alan Shields, Electronic Diaries: Applications and What Works in the Field, 

 April 2002, 4656. 
5. Guideline for Good Clinical Practices, International Conference on Harmonization, Federal Register, Section 1. Glossary (www.emea.eu.int/pdfs/human/ich/013595en.pdf).
6. Paul Bleicher, eSource Redux, 

 August 2002, 3031.
7. Arthur Stone, Saul Shiffman, Joseph Schwartz, Joan Broderick, and Michael Hufford, Subject Non-compliance With Paper Diaries, 

 324 (2002), 1193-1194.
8. Saul Shiffman, Celeste Elash, Stephanie Paton, Chad Gwaltney, Jean Paty, Deborah Clark, Ken Liu, and Michael DiMarino, Comparative Efficacy of 24-Hour and 16-Hour Transdermal Nicotine Patches for Relief of Morning Craving, 

 95: 11851195 (2000).
9. International Conference on Harmonization, ICH Guidelines, Good Clinical Practices, Section 5. Sponsor (www.emea.eu.int/pdfs/human/ich/013595en.pdf).
10. Food and Drug Administration, Guidance for Industry: Computerized Systems Used in Clinical Trials (FDA, Rockville, MD, 1999).
11. Code of Federal Regulations, Title 21 CFR, Part 11: Electronic Records; Electronic Signatures; Final Rule, Federal Register, March 20, 1997.
12. Paul D. Lepore, FDAs Good Laboratory Practice Regulations and Computerized Data Acquisition Systems, 

Experts discuss the use of subject diaries and the way researchers can comply with applicable regulations and guidelines.

Electronic Diaries, Part 1: What Is a Subject Diary, and How Do Regulations Apply?

In June, the House of Representatives approved a Medicare reform bill that provides a prescription drug benefit for seniors. The Senate tried to forge a compromise Medicare coverage plan, but in the end settled for other measures designed to make prescription drugs more affordable for all consumers. This includes a bill to revise patent laws to bring less expensive generic drugs to market more quickly, as well as policy changes to ease imports of cheaper medicines. Manufacturers vigorously oppose these initiatives as a threat to continued private sector investment in biomedical research. The Bush administration appears sympathetic to industrys stance. It has opposed a too-costly Medicare drug benefit and proposals that soften import controls and open the door to terrorists.


Any legislation to establish a Medicare drug benefit will be expensive. Even the relatively low-cost House Republican Medicare bill (H.R. 4954, passed by the House 27 June 2002) allots about $310 billion over eight years for a Medicare pharmacy benefit, plus another $30 billion to boost Medicare payments to hospitals, doctors, and HMOs. Some Senate proposals carry price tags double that amount. All these figures are likely to increase exponentially as the U.S. population ages and consumes more medicines to treat chronic conditions.

Pharmaceutical and biotech companies prefer the Republican approach that permits Medicare beneficiaries to purchase prescription drug coverage from private insurance companies, instead of establishing a new benefit program run by the Department of Health and Human Services (HHS). The House bill would limit government expenditures by imposing fairly high co-pays, premiums, and deductibles on Medicare beneficiaries up to a $3700 annual catastrophic limit. There are subsidies for low-income seniors. Additionally, HMOs and pharmacy-benefit managers that manage Medicare drug plans can establish formularies, tiered co-pays, and restrictive pharmacy networks to control costs.

Democrats rejected the House Republican bill as a scam because seniors would pay more than $4000 annually out of pocket for full coverage; Republicans countered that the Democrats approach could bankrupt the federal budget. The best outcome would be legislative gridlock, says 

 columnist Robert Samuelson. Although a Medicare drug benefit makes sense, current legislation offers no provisions to pay for it. Unless Congress curbs mounting long-term retirement costs by raising the Medicare eligibility age and reducing benefits for wealthier seniors, future workers will face huge tax increases, Samuelson observes. Until then, political paralysis is a better course.


A more attractive alternative for many legislators is to approve other measures to curb rising drug prices. Such bills would help consumers pay for medicines and reduce potential government expenditures for a Medicare drug benefit. During debate over the House Medicare bill, members of both parties tried to add provisions to permit reimport of low-cost medicines from Canada and to revise generic drug patent policies. The House leadership blocked these issues from cluttering up their Medicare bill, but Senate Democrats moved forward. 

In July, the Senate approved a generic drug competition bill that makes significant changes in the Hatch-Waxman Act of 1984. The measure aims to lower costs by preventing innovator firms from using patent policies and regulatory procedures to block new generic competition. A compromise version of the legislation (S. 812) limits 30-month patent extensions for brand-name manufacturers that file lawsuits against generic drug makers for alleged patent infringement, plus revises the 180-day exclusivity policy available to generics firms. A new and highly controversial provision would allow generics makers to file suit challenging inappropriate patents in FDAs Orange Bookbut not collect monetary damages. There also was heated debate over language giving FDA authority to revise bioequivalence standards for generics, which biotech companies feared would open the door to approval of nontraditional (biotech) generic products. 

Even if Congress fails to revise generic drug policy this year, the FDA budget bill for 2003 may address some of these issues. The spending bill approved by House appropriators expands FDA resources to speed up approval of new generic therapies and calls for FDA to clarify criteria for Orange Book patent listingsinitiatives designed to reduce delays for bringing new generic drugs to market.


The Senate generic reform bill included a  measure that loosens curbs on drug reimporting so that consumers may obtain low-cost foreign medicines more easily. Members of Congress, particularly those in border states, backed legislation allowing individuals, pharmacists, and wholesalers to reimport FDA-approved drugs from Canada. Congress approved a broad reimport bill two years ago, but FDA said it could not implement it and still ensure that imported drugs were safe and effective. Limiting reimport to Canadian products aims to address regulatory concerns, but FDA officials still protested that any import expansion will let a flood of unregulated and unsafe medical products into the United States. And fear of U.S. vulnerability to bioterrorism attack has further heightened these concerns. 

FDA aired its objections at a July hearing before the Senate Special Committee on Aging. FDA senior associate commissioner Bill Hubbard strongly opposed reimport proposals, noting that the federal government already faces a massive task in checking for illegal drug imports at the nations ports and through the mail. Although members of Congress intended to provide drug price relief to consumers, Hubbard said that the proposed legislation would severely damage the FDA regulatory system. Panel chairman Senator John Breaux (Democrat, Louisiana) linked reimport proposals to the rising tide of drug counterfeiting. FDA has uncovered a growing number of phony products with faulty labeling, no active ingredient, or wrong ingredients.

Hubbard blamed the recent surge in mail volume containing illegal drug imports partly on the growth in Internet drug sales. Many Web sites dispense expired, subpotent, contaminated, or counterfeit products. FDA has 90 Web sites under active review, and its Office of Criminal Investigations has initiated 296 Internet drug probes; there have been arrests, convictions, and multimillion-dollar fines.

Although personal import of unapproved drugs is a serious concern, FDA officials are more disturbed by the emergence of global operators bringing counterfeit, adulterated, and substandard products into the U.S. market. FDA opened 55 counterfeit drug cases over the past 4 years, which have led to 26 arrests and 20 convictions. But the trend is growing, Hubbard noted, with 16 new cases and 12 arrests so far this year. In May 2002, Serono Laboratories (Rockland, MA) detected counterfeit versions of Serostim (somatropin) that contained no active ingredient and had fake lot numbers. Vials of Neupogen (Amgen, Thousand Oaks, CA, filgrastim) appeared last year containing only saline solution and with erroneous lot numbers and incorrect expiration dates. Counterfeit versions of Amgens Epogen (epoetin alfa) had active ingredient levels 20 times lower than appropriate. Pfizer (New York, NY) has launched a major campaign to detect counterfeit Viagra all over the world.

FDA is upgrading its computer data systems to obtain better information on product imports and is looking at new technologies, such as x-ray devices, and other safeguards that may help law-enforcement officials deal with rising illegal import volume. The task will be that much harder if Congress liberalizes import rules. 


With Congress slow to enact a Medicare drug benefit or curbs on drug prices, state health agencies have expanded pharmacy benefit programs for low-income consumers to fill the Rx benefit gap. Many states are approving new cost-cutting strategies that call for manufacturers to offer more discounts beyond Medicaid rebate requirements, actions that have prompted lawsuits from industry.

HHS approved a plan for Michigan last January that seeks to induce pharma companies to offer supplemental rebates by establishing a formulary identifying best-in-class treatments in each therapeutic category. Companies that refuse to lower prices to meet the lowest class price dont make the preferred list and require prior authorization for doctors to prescribe the medicine. Most physicians wont bother, which would help the state save a projected $800,000 a week and $50 million annually. 

Manufacturers claim the Michigan program violates Medicaid policy because its new formulary excludes hundreds of drugs from manufacturers that already have entered into Medicaid rebate agreements with HHS. The program will restrict patient access to the most innovative, life-saving drugs and biologics, BIO president Carl Feldbaum wrote Michigan governor John Engler last year. PhRMA filed a lawsuit in June to block implementation of the program, largely because 11 more states have adopted similar policies, and others say they will do so. 


Debate over whether a state may impose such prior authorization restrictions on Medicaid patients in order to extend pharmacy coverage to non-Medicaid beneficiaries is a key issue in the Michigan suit and in another case involving a Maine pharmacy plan that the Supreme Court has agreed to review next term. The state approved its Maine Rx plan two years ago, but PhRMA legal action has blocked implementation. Manufacturers oppose the states demand that they pay additional rebates in order to avoid Medicaid-like prior authorization restrictions on their products. A Federal District Court agreed with industry that the program violates Medicaid policy, but a Federal Court of Appeals overturned it in May 2001. PhRMA appealed to the Supreme Court, which decided to hear the case despite opposition from the Bush administration. The Senate approved a measure in July that allows states to adopt rebates and other cost-cutting provisions. If the bill becomes final, it could affect these and other legal battles involving pharma prices and patents.


1. Robert Samuelson, Pray for Gridlock, Washington Post (10 July 2002).

SIDEBAR: Bush Backs Competitive Pharmaceutical Market as Key to Innovation

As the debate on a Medicare drug benefit and other cost-control proposals was heating up on Capitol Hill in July, president George Bush unveiled a report from HHS documenting the importance of new drug and biotech R&D in improving the health of the elderly, titled Securing the Benefits of Medical Innovation for Seniors: The Role of Prescription Drugs and Drug Coverage, (aspe.hhs.gov/ health/reports/medicalinnovation/). The study credits strong government support for biomedical research plus reliance on private health insurance coverageas opposed to government price controlsfor giving Americans access to most new medical products. The open U.S. market has encouraged private sector investment in R&D that has spurred medical innovation.

The report cites numerous examples of restrictions on patient access to newer drugs in countries that rely on government controls to keep down drug prices and reimbursement. In many cases, foreign authorities delay or deny regulatory approvals or insurance coverage for new therapies largely to limit spending. The study presents a long list of newer treatments for osteoporosis, cancer, asthma, arthritis, high cholesterol, and heart disease that are available in the United States but not in all other countries. The main message is that government control of prescription drug pricingas proposed in Democratic Medicare drug benefit billscould deny the elderly access to important medical innovations likely to enhance their lives.            

View from Washington

Although a Medicare drug benefit appears unattainable this year, Congress is considering other measures to reduce the cost of medicines.

Coping with the Cost of Prescription Benefits

The European Organisation for Research and Treatment of Cancer is dedicated to improving cancer treatment in Europe. Its Regulatory Affairs Unit provides important services to researchers.

EORTC's Regulatory Affairs Unit

Adaptive interim analysis may allow smaller sample sizes when a drug?s clinical effect is unknown.

Using Adaptive Interim Analysis to Calculate Sample Size in a Trial of a Treatment for Erectile Dysfunction

Lynn Sadowski is a senior clinical research associate at Sention Inc., 4 Richmond Square, Providence, RI 02906, (401) 272-7177, email: lsadowski@sentionpharma.com.

If youre a monitor, one of the most important relationships youll ever have is with the coordinators of your sites. After all, when the database is about to be locked, and you need one final data clarification form (DCF) completed and returned to you in three hours, its the coordinator to whom you beg and plead for assistance. Past experience tells you that the coordinator is your go-to player when you need something done. You want to make sure that this go-to player is on your side.

Although much of this is common sense, it seems worth repeating. In our worlds of connecting flights, DCFs, lost reservations, and visit reports, sometimes some of the finer points of relationship-building are left on the plane with the empty bag of snack mix we had for lunch.

In order to build and maintain your relationships with your coordinators, you need to use both technical and personal methods. Early on, the technical methods that you are going to use to build your relationship will be to provide training and define expectations and roles in the study. In order to maintain the relationship you will continue to use these technical methods by providing ongoing training, providing support for the site, and making sure that you wear your monitoring hat when you visit the site.

The personal methods may be a little more obvious, but nonetheless, are worth repeating. Early on, you will want to develop a personal relationship with your sites in order to break the ice. The easiest way to do this will be to get to know your coordinators outside the clinic walls. In order to maintain this relationship, you must make sure that each coordinator feels appreciated. Recognize the efforts that have been made for your study, and provide feedback both verbally and in writing.


During your first meetings with the coordinators, you can use the following methods to build the monitor-coordinator relationship:

 both yours and theirs. You are a regulatory guru. You are a master of the protocol at hand. The coordinators are the experts in the disease that you are working in, experts in the operation of the units that you are monitoring, and experts in the subjects enrolled at the sites. To complete the study successfully, you need to find a way to tap into both your strengths and the strengths of the coordinators.

To accomplish this goal, you need to form a team with your coordinators. And by all means, let the coordinators know what their role in this team is going to be. Ask the coordinators questions about the disease background, ask their opinion on issues, and work with them to develop resolutions to noted issues.

Nobody likes a monitor who comes to his or her site and says, Do this, and do that. Making the coordinators active participants will help them feel like a part of the team you are trying to form. Ultimately, this will lead to a more effective and more productive working environment.

 Take the time during the qualification and initiation visits to assess the knowledge base of the coordinators. If the coordinators dont know how to consent subjects, randomize subjects, complete source documentation, complete the case report form, and dispense the medications after the initiation visit, they arent likely to do it right when the study begins. Nobody wants to author (or monitor, for that matter!) a truckload of Notes to File detailing all the mistakes that were made that could have been prevented through training.

This is not to say that training should end at the initiation visitreeducation and training should take place at every monitoring visit. Remember, your job is to give every one of your sites the tools that they need to successfully complete an FDA audit. If you fail to do this, you have done an injustice to your study, and most importantly, to your site.

 Nobody is a mind reader. You need to be very clear about what your expectations are, both verbally and in writing. If you expect all corrections requested at a site to be made to the case report forms before the next monitoring visit, tell the coordinator that, and write it in the follow-up letter.

Also be very clear about what the coordinators can expect from you. If you are going to assist the sites in generating Notes to File, notifying their IRB of issues, or revising regulatory documents, make sure you let the coordinators know this.

In order to work as a team, monitor and coordinator both need to know what the other person is doing. Defining your expectations of each other will ensure that all needed tasks are accomplished, and that efforts are not duplicated.

 I am not suggesting that you spend evenings drinking margaritas with your coordinatorsyou need to maintain a professional boundary. I am suggesting that you simply make an effort to communicate with your coordinators on a personal level. Make it a point to ask your coordinators about their weekend activities or plans, or their families.

Ultimately, the more comfortable your coordinators are with you, the more likely they are to call you with a question or a problem, rather than letting it fester until you uncover it at your next visit.


After your relationship is established, you can use several methods to maintain that relationship.

Readers like Lynn Sadowski, a senior clinical research associate at Sention Inc., share their experiences.

Applied Clinical Trials-09-01-2002