The expansion of government reimbursement for prescription drugs under the Medicare drug benefit is increasing interest in obtaining more comparative information on drugs and medical products. In addition to the basic safety and efficacy data produced in pre-approval clinical trials, payers want evidence on how a new drug compares to existing therapies and whether it is cost effective. Recognizing that prescription drug coverage for seniors would drive up utilization and spending, the Medicare Modernization Act of 2003 supports more independent research on comparative drug effectiveness; the aim is to limit reimbursement by the Center for Medicare and Medicaid Services (CMS) to those products that demonstrate clinical advantage over available medicines and to reduce inappropriate spending. 

This demand for comparative effectiveness information to gain coverage by public and private payers is affecting biomedical R&D. There has been considerable talk about CMS playing a more visible role in the FDA's drug approval process to accelerate patient access to some new therapies. However, there are concerns that demanding more comparative and effectiveness information from pre-approval testing programs could make drug development even longer and more costly. 

Even though regulators agree with industry that a formal coordinated review process is not advisable, manufacturers of drugs and medical devices are consulting more often with CMS early in the development process. Sponsors want to avoid surprise last-minute information requests, such as additional safety data for certain population subgroups. FDA also is working more closely with CMS in preparing guidance on certain research issues, such as the use of pharmacogenomic tests with personalized medicines. CMS and FDA are crafting a memorandum of understanding that permits the two agencies to share proprietary information if needed to accelerate reimbursement decisions. 

Moreover, CMS' Coverage with Evidence Development (CED) program is shaping drug development and utilization decisions more directly. This controversial initiative authorizes Medicare reimbursement for a drug or medical procedure provided that the sponsor collects additional effectiveness information through clinical trials, patient registries or other assessments. While CMS officials paint this approach as expanding payment for "promising but not persuasive" uses of drugs and medical products, pharma companies are wary that Medicare will routinely require postapproval studies as a condition for new drug reimbursement. 

The CED program also has raised ethical questions about protecting the rights of elderly patients who may be pressured to provide personal treatment information in order to obtain coverage for recommended care. Last year, CMS decided to cover four colorectal cancer therapies for off-label uses, but only for patients enrolled in certain clinical trials sponsored by the National Cancer Institute. CMS also proposed to greatly expand the use of PET (positron emission tomography) imaging for diagnosis and staging of a broader range of cancers for those patients who submit data to a PET imaging registry. Although the PET coverage plan seeks to better understand how imaging affects treatment decisions, the program was placed on hold for several months when concerns arose that it could coerce seniors into providing confidential treatment information in order to gain access to scanning services. 

Such criticism has prompted CMS officials to revise its draft guidance on the CED program, and a new document has been promised this year. Meanwhile, CMS and the radiologists developing the PET registry devised an alternative process for collecting treatment data on nonconsenting patients. The initiative also avoids extensive informed consent procedures and oversight by IRBs at some 800 participating facilities. 

Less controversial is another CED registry to track the effectiveness of implantable cardioverter defibrillators (ICDs) in preventing fatal heart attacks. CMS decided to cover ICD use more broadly in January 2005, and required patients receiving these implants to enroll in the National Cardiovascular Data Registry developed by the American College of Cardiology and the Heart Rhythm Society; it is gathering data on all patients (not just Medicare beneficiaries) receiving ICDs at 1300 hospitals. With more than 125,000 ICDs implanted annually in the United States, the registry expects to collect considerable information. 

CMS anticipates that the ICD registry will be the "poster child" for its CED policy, commented CMS special advisor Steven Pearson at a May conference on evidence-based medicine sponsored by Avalere Health. Registration of patients at the time of service should ensure that treatment is targeted to individuals most likely to benefit; data review should point out key differences in outcomes for different providers, devices, drugs, and patients; and all this information should be useful in developing pay-for-performance programs that reward physicians able to provide higher quality care.  

These initiatives reflect increased interest in using patient registries to obtain more outcomes information on innovative treatments. This approach may gain wider acceptance with the development of a reference guide on patient registries by the Effective Healthcare Program at the Agency for Healthcare Research and Quality (AHRQ). The agency has posted on its Web site an outline to this guide on establishing, maintaining, and evaluating registries that collect information on patient outcomes following medical treatment, and a final version from consultant Outcome Sciences is due by year-end. The guide will provide case studies on effective trial registries and will address many of the patient protection issues that surfaced related to the PET scan registry. 

While sponsors feel pressure to develop more outcomes information, government-sponsored comparative effectiveness reviews of widely used drug classes are emerging from Evidence-based Practice Centers (EPCs) established by AHRQ's Effective Health Program. A May report comparing drugs to treat anemia in cancer patients, for example, finds little differences in safety and effectiveness. Another review similarly concluded that most second-generation antidepressants have few differences in main effects and adverse events.  

States and consumers also seek more evidence to support the use of new medical products. The Drug Effectiveness Review Program (DERP) administered by an Oregon evidence-based policy center provides pharmacy clinical reviews to 15 state Medicaid programs and other organizations. Such information helps states compile preferred drug lists for Medicaid and other state pharmacy programs. 

In the international arena, the National Institute for Health and Clinical Excellence (NICE) in the United Kingdom has made cost-effectiveness analysis an acceptable part of the evaluation process for drugs, particularly those therapies that raise coverage questions due to high cost or uncertain effectiveness, pointed out NICE Chief Executive Andrew Dillon at the May conference. This institute conducts technical appraisals of new drugs and medical procedures that consider both clinical and economic issues; final recommendations are for routine or selective drug use or use only in a research setting. A recent high-profile assessment recommends use of aromatese inhibitors to treat beast cancer. NICE also is expected to issue a guidance this summer on appropriate use of Herceptin for early-stage breast cancer. Because the UK health system has a fixed budget, Dillon explained that a local health service that wants to pay for a very costly drug has to cut back somewhere else. 

One unintended consequence of expanded payer support for more information on real-world drug effectiveness may be to discourage manufacturers from conducting post-approval studies needed to gain FDA approval of new indications. FDA Deputy Commissioner Scott Gottlieb pointed out that if government and private health plans decide to cover an unapproved drug based on their own analysis, sponsors have less incentive to underwrite studies needed to put a new indication on the product label.  

This development would only increase off-label drug use, which often is inappropriate, according to another study sponsored partly by AHRQ. An article in the May 8, 2006, issue of the 

 finds that about 21% of drug use in 2001—some 150 million prescriptions—was for off-label uses; most alarming is that 73% of those off-label uses had "little or no scientific support."  

Industry and FDA officials contend that much off-label prescribing is appropriate. Physicians are highly protective of their right to prescribe drugs off label, particularly for children and cancer patients. FDA does not conduct any specific assessment of off-label uses and limits the practice only by challenging industry-sponsored promotions. But requirements could stiffen if policymakers agree that there is a need for more surveillance and further analysis of the clinical and economic implications of such "non-evidence-based prescribing."  

Articles

View from Washington

Payers seek more comparative drug data from sponsors and independent researchers.

Demand for Evidence Drives Research Process

Any regular commentary on the environment for the pharmaceutical industry in Europe is bound to have a predominantly negative tone, so it is a welcome change to be able to record a positive development in the regulatory context—and one that should make life a little easier for everyone involved in developing new medicines. 

Starting July 1st, the European Medicines Agency is changing the way it provides scientific advice on the research and development of new medicines, including assistance on protocols. Sponsors can expect final advice after as little as 40 days, and certainly within 70 days—compared to the previous 100-day procedure. The experts will be involved earlier and more systematically. The agency's Scientific Advice Working Party is being expanded from 22 to 26 members. 

And with the same attention to broadening the relevance and legitimacy of the advice, internal assessors will be backed up by more external experts. For example, the agency is introducing a formal peer review of advice before it is issued, to maximize clarity and to ensure consistency. It is also ensuring closer collaboration with academia, learned societies, and patient organizations. 

At first sight this might not seem so momentous. But it represents another important step in bridging the gap that regulators in Europe have been trying to straddle for nearly half a century. 

From the very first steps in European-level drug regulation, which led in 1965 to the first EU directive on pharmaceuticals, a theoretical balance has been sought between making drugs safe and making drugs available. But for decades, as EU drug legislation evolved, the emphasis was very much more on the safety aspects, while getting useful new treatments onto the market was relatively neglected. As Pierre Joly, the larger-than-life boss of Roussel Uclaf and long-time president of the French drug industry association, famously remarked back in the 1980s: "If the pharmaceutical industry was building a car, they'd start by designing the engine. But the regulatory authorities would start by designing the brakes." 

In recent years, this trend has been gradually modified, as the once-unchallenged supremacy of the European pharmaceutical sector came under increasing attack from global competitors and as its share of innovation started to decline. Even the most conservative regulators started to notice that not only were the brakes they had designed very effective, but that the motor was misfiring and in need of maintenance. 

Intermittently, but increasingly, the authorities in Europe admitted that a one-dimensional view of the role of regulator was not enough. The needs of patients would not be best served if new drugs were systematically kept off the market. The art of the exercise came to be seen not just as excluding new drugs with inadequate merits, but in providing a context conducive to the emergence of demonstrably effective medicines. The underlying philosophical drift was from confrontation to collaboration—or, in that overworked phrase, synergy. 

One of the consequences was the explicit stress in the last major revision in 2004 of the EU's pharma rules on improving the competitiveness of European-based research and development of medicines. And although much remains to be done in that direction—particularly on the economics of drug provision in Europe—there has been a perceptible shift in the approach of the Medicines Agency. 

The agency, which by its nature is at the sharp end of so many critical decisions on the development of individual drugs, has made a priority out of providing scientific advice to sponsors, whether pharmaceutical industry or other researchers. It aims to help sponsors to develop new medicines faster and more effectively, "which, ultimately, helps to speed up access of patients to innovative new medicines," it openly states in the announcement of its modified "Framework for Scientific Advice & Protocol Assistance." 

The Scientific Advice Working Party is now a formal EU body, with the sole remit of providing scientific advice, particularly regarding the development of new therapies. It includes specific expertise in preclinical safety, pharmacokinetics, statistics, and therapeutic fields for which there are frequent requests (such as cardiology), as well as in fields already defined by the EU as priorities: oncology, diabetes, neurodegenerative disorders, and infectious diseases including HIV. Because of its growing workload—in 2004 it dealt with 109 requests, twice the number of the year before—it has been meeting for two days a month on a regular basis, and it will now meet for three-day sessions. 

Scientific advice may be requested for all human-use medicines, whether or not their degree of innovation makes them eligible for the EU's centralized procedure. Protocol assistance is available for designated orphan medicinal products. The requests entertained by the working party stretch widely, covering practically everything except for pre-assessment of data to be used to support future marketing authorization applications, and they must relate to the scientific aspects of product development. This means they can cover chemical, pharmaceutical, and biological quality testing; toxicological and pharmacological nonclinical tests; and clinical studies in either patients or healthy volunteers, including clinical pharmacological trials to determine efficacy and safety pre- or postauthorization. The assistance on protocols extends to questions about demonstrating significant benefit within the orphan indication and about similarity or clinical superiority in relation to other orphan products with market exclusivity. 

The new procedures will be more flexible, making it easier, for instance, for sponsors to seek follow-up advice. The broadened definition of a follow-up request is meant to be an incentive to encourage applicants to seek scientific advice or protocol assistance as many times as necessary throughout their development program—that way, continuity in the agency's support of the development of their product can help reduce the uncertainties of the marketing authorization process. There will also be measures to provide incentives to smaller firms. The new framework is intended to allow more interaction with sponsors by providing new dialogue phases and opportunities for feedback, and by intensifying protocol assistance, which is of particular value to smaller firms and sponsors developing emerging therapies. 

The new procedure makes explicit the growing acceptance of synergy. "The main stakeholder of scientific advice is the pharmaceutical industry. However, since better scientific advice means better, more effective, and faster development of safe and effective medicines, scientific advice is ultimately beneficial to patients and health care professionals as well," says the agency's announcement. It is a valuable acknowledgement of an underlying but underestimated factor in new medicines provision. 

Meanwhile, the agency has not given up its day job. It is continuing to assess applications and to issue guidance on how broader new problems relating to applications should be approached. To address one of these emerging questions, it has issued a concept paper to promote discussion on the use of genomics in cardiovascular clinical trials. This has arisen from agency awareness of the growing volume of reflections on how drug efficacy can be influenced by patients' genetic background—including susceptibility to develop diseases, genetic variations in drug targets, physiological counter-regulation effects, and drug tolerance. 

The problem the agency is drawing attention to is that most scientific studies are inconclusive as to whether a clear association can be established between genetic traits and outcomes of cardiovascular disease treatments. The current state of knowledge of the polymorphisms relevant to cardiovascular diseases does not appear sufficiently mature, particularly because of the fragmented knowledge that is acquired with the type of clinical trials undertaken so far, says the agency. It is convinced that newer, more robust approaches for generating pharmacogenetic data from clinical trials in the cardiovascular field are needed. 

As a response, it is proposing to conduct a critical review of the experience from clinical trials that explore the association of genomic traits in response to medicines in the cardiovascular diseases area. This could serve to help future applicants by setting out general scientific principles for clinical trials incorporating genomic variables.  

is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium. 

View from Brussels

European Medicines Agency adopts new approach to drug development process.

Bridging the European Regulatory Gap

Investigators within the European Union who plan to design, conduct, record, and/or report clinical trials with medicinal products have to meet the principles of good clinical practice (GCP). All drug trials involving human subjects must be scientifically sound and guided by internationally recognized ethical principles to protect the rights, safety, and well-being of clinical trial participants. The Clinical Trials Directive 2001/20/EC

  and the Good Clinical Practice Directive 2005/28/EC,

  developed over the last few years, are two European directives that support the ethical principles of good clinical practice. 

Before these principles of good clinical practice were incorporated into the European legislation, they were developed as guidelines for the International Conference on Harmonisation (ICH)

 ; the ICH brings together the regulatory authorities of Europe, Japan, and the United States and experts from the pharmaceutical industry in the three regions. This ICH-GCP Guideline was developed in order to provide a unified standard for clinical drug trials taking place in the EU, Japan, and the United States. The objective of such a harmonization was to facilitate the mutual acceptance of clinical drug trial data by the regulatory authorities in these three jurisdictions. The guideline was created to reduce or even obviate the need to duplicate preclinical and clinical testing of new medicines and to use human, animal, and material resources more economically. Furthermore, the guideline was compiled to eliminate unnecessary delay in the global development and availability of new medicines and to maintain at the same time safeguards on quality, safety, and efficacy and regulatory obligations to protect public health. The ICH-GCP Guideline was subsequently adopted by the European Medicines Agency (EMEA),

  and the principles of good clinical practice were incorporated in the previously mentioned directives.

Since the incorporation of the guidelines in European directives and their subsequent mandatory implementation in the national legislations of the individual member states of the EU, they are legally binding throughout the European Union. 

This is a new situation, especially for clinical researchers who conduct noncommercial clinical drug trials without the participation of the pharmaceutical industry, otherwise also referred to as investigator-initiated trials (IITs). These clinical investigators, who mainly work at university hospitals and private practices, constitute a large group of physicians who need to be trained and educated in order to be able to apply the principles of good clinical practice in IITs to the full extent. Hari 

It is important to know that the "Good Clinical Practice Directive" literally demands that "each individual involved in conducting a trial shall be qualified by education, training, and experience to perform his tasks."

  Moreover, the directive reads that the ethics committee, when making up its opinion on a clinical trial, "shall consider in particular [...] the suitability of the investigator and the supporting staff."

The principles of good clinical practice have been established to set an international standard for clinical drug trials. However, it is sensible to apply their methodology also—where applicable—to other clinical investigations (e.g., trials on surgical and diagnostic procedures) in order to safeguard the well-being of human subjects and the quality of data. It is advisable to do so because no comparable principles have been developed yet for other types of clinical research. Thus, even clinical researchers who want to investigate other problems or questions other than medicinal products would be wise to become familiar with the principles of good clinical practice. 

In summary, there is now an increased need for training opportunities with respect to the highly complex field of clinical research in the European Union—no matter whether clinical trials with or without investigational medicinal products are concerned. In order to fill this gap, the EU project CLEAR (clinical research physician) was created. Within this project, a European-wide, uniform postgraduate training program for clinical investigators has been developed. Its purpose is to impart the necessary knowledge about GCP, including a great variety of useful and helpful tools like biometrics and statistics or clinical and preclinical basics. The CLEAR project is now entering the phase of first pilot courses and will be further described below. 

Thirteen partners from the following seven European countries participate in this EU project: Austria, Cyprus, Germany, Greece, Hungary, Ireland, and Latvia.  

The expertise that the different CLEAR partners bring with them into the project range from teaching, preclinical and clinical research, biostatistics, postgraduate training and seminar activities (e.g., courses for clinical investigators

  organized by the Coordination Centre for Clinical Trials at University Hospitals Tübingen and Ulm—KKS-TU GmbH, formerly KKS-UKT gGmbH) to didactical and methodical experience, as well as the capacity to realize eLearning concepts. Furthermore, the knowledge of various partners in the fields of quality assurance, accreditation of postgraduate education, national and international dissemination strategies, marketing, business development, and international project management is important for the success of the project. 

The work of the CLEAR team is accompanied by an independent scientific board. The members of the board are experienced scientists who come from several European countries. They support the development of the project and ensure that the CLEAR team provides up-to-date, scientifically sound and quality-assured training materials. 

CLEAR is financially supported by the European Commission's vocational training program "Leonardo da Vinci." This program promotes transnational projects based on cooperation between the various participants in vocational training in an effort to increase mobility, foster innovation, and improve the quality of training. It is a key instrument in the drive to implement lifelong learning strategies that offer synergies between European policies for training and employment.

 Table 1. Contents of Module "Preclinical and Clinical Basics."			

The CLEAR course is intended for all physicians and other persons who want to perform clinical research involving human subjects irrespective of the type of clinical study. Although CLEAR is particularly suitable for investigators concerned with clinical drug trials since the emphasis of the training program is on the principles of good clinical practice, CLEAR is also of great value for researchers performing clinical trials other than drug trials. That is because the methodology for clinical drug trials is the best one developed and can therefore be used as a model for all other sorts of clinical trials—where applicable—for the reasons explained above. 

Table 2. Contents of Module "Planning and Organization."			

CLEAR offers an excellent opportunity to gain the required theoretical knowledge and take an important step forward in acquiring the necessary qualification as clinical research physician—which, in addition to theoretical knowledge, also demands a certain amount of experience in performing clinical research tasks. 

Table 3. Contents of Module "Law and Ethics."			

The content of the CLEAR curriculum covers all major topics relevant for investigators responsible for or collaborating on all sorts of clinical trials, with the main focus on clinical drug trials. The many complex aspects of clinical trials covered in the CLEAR course are structured into four modules: Preclinical and Clinical Basics, Planning and Organization, Law and Ethics, and Statistics and Biometrics. Tables 1–4 describe the curriculum contents of each module. 

Table 4. Module "Statistics and Biometrics" contents.			

The content of the CLEAR curriculum is implemented via the so-called blended-learning method, which combines traditional face-to-face seminars with eLearning. In the case of the CLEAR course, a CD-ROM has been developed to deliver the learning program. 

Table 5. Institutions and members of the CLEAR team.			

The structure of the CLEAR CD-ROM mirrors the four modules of the curriculum. For each of the modules there is a section with detailed background information, which allows the user to either acquire new knowledge or deepen existing knowledge or to look up something quickly to solve a specific question. All texts are illustrated with loads of examples to make complex issues more understandable. In addition, a three-part library containing literature references, online resources, and a glossary can be consulted. In order to enable the learner to check his or her own knowledge and to create references to real-life situations, a large number of case studies is incorporated. Furthermore, a great variety of interactive exercises are awaiting the user. They range from multiple choice questions over drag and drop tasks to cloze exercises. 

The fact that part of the CLEAR curriculum is imparted via eLearning enables CLEAR participants to work through the four modules at their own pace, as often as they like and whenever it suits them. The obvious advantages of eLearning will certainly be valued by the target group of CLEAR, which mainly consists of hospital and private practice physicians, who on the one hand have high professional standards and are used to studying on their own, and who on the other hand frequently lack the time for attending a lecture series or week-long seminars for further professional training. 

Nevertheless, parts of the CLEAR curriculum are taught in classic face-to-face lessons to achieve optimal learning results. The presence of a lecturer and other course attendees can enhance the pleasure of learning and encourage the participants to ask questions or to discuss with each other. Thus, the advantages of eLearning are complemented by the advantages of face-to-face seminars in the CLEAR course. 

All eLearning materials of the CLEAR course are currently available in two languages: German and English. The English version of the CD-ROM has been produced to allow its use in all European countries no matter the native language. 

Since the face-to-face seminars can be taught in whatever language is desired, the CLEAR course is truly multilingual. 

At the end of the CLEAR course, the participants have to pass a written final examination in order to get a certificate of attendance. This test serves to check the knowledge acquired during both the face-to-face classes and the eLearning lessons. 

Due to the good results of the pilot courses, it has been decided to further develop this unique European, multilingual, postgraduate training program for clinical research physicians. In order to increase the possibilities of CLEAR, plans are underway to transform the eLearning parts from the computer-based program to a Web-based training program. In addition to such advantages as more interactivity between participants and tutors, this will facilitate the necessary continual updating of the contents. The CLEAR project homepage provides continuously updated information on its current status.

The institutions (and members) of the CLEAR team are listed alphabetically in Table 5. 

The CLEAR project is financially supported by the European Union (Agreement No 2003-A/03/B/F/PP-158.023). 

1. European Parliament and Council of the European Union, "Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations, and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use," 

2. Commission of the European Communities, "Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing and the importation of such products," 

3. Guideline for Good Clinical Practice, ICH guideline, efficacy topic E6, available at: 

Feature Article

This new course aims to provide clinical research physicians with good clinical practice knowledge.

CLEAR: An EU Postgraduate Training Program

With cancer estimated to be the leading killer of Americans aged 55 and older, and the aging baby-boomer population reaching 60 this year, the call for life-saving drugs is stronger than ever. It has been estimated that 570,000 people were expected to die from cancer in 2005.

  This has led to an influx of pharmaceutical companies entering the field in the quest for cancer curing drugs, which in turn has made oncology one of the fastest growing clinical monitoring sectors. The generic cancer market alone is expected to grow at an impressive compound annual rate of 23.5% from 2004 to 2014.

The nation's changing demographics also play a role in oncology trial growth. Studies from the Centers for Disease Control and Prevention show that 76% of all cancers diagnosed are found in people 55 and older. So, as the baby boomers approach 60, the instances of cancer in the United States are expected to increase dramatically. Also, while only one in 12 men and women will develop cancer between the ages of 40 to 59, the instances jump to one in three men and one in four women between ages 60 to 79.

In addition to such rapid growth and interest from companies in oncology, other parties are taking a serious interest as well. Coverage of patients' rights issues has become a fixture in the media and has fueled the already politically charged environment. As a result, the FDA is more watchful than ever during these trials. With the creation of the Drug Oversight Safety Board in February 2005, the FDA will oversee the management of important drug safety issues within the Center for Drug Evaluation and Research (CDER). 

The FDA will also increase the transparency of its decision-making process by establishing and expanding communication channels to provide targeted drug safety information to the public. These channels will be used to help ensure that established and emerging drug safety data are quickly available in an easily accessible form. The increased openness will enable patients and their health care professionals to make better-informed decisions about individual treatment options. As the FDA develops these communications formats, it will also solicit public input on how to manage potential concerns associated with disseminating emerging information prior to regulatory action.

With the recent expansion in the number, complexity, and longevity of oncology trials, companies are requiring greater skill sets and more experience from the individuals who are responsible for the clinical trial monitoring. The increased scrutiny placed on the clinical trials has resulted in increased responsibilities for the clinical research associate (CRA). Pharmaceutical companies must take a more specialized approach in staffing these highly skilled and trained professionals for oncology trials. What's more, due in part to their long-term nature, the complexity of the disease, and increase in cancer biomarkers, oncology trials collect more data points than any other trial type. 

CRAs must fill a checks and balances role in oncology trials, ensuring that the investigator follows proper protocol in defining how the drug affects the patient. For example, an investigator may report that a patient responded positively to a particular drug. However, that determination may have been made through criteria that do not match those set out by the protocol for the trial. In that case, the CRA must note any deviations with proper documentation, address them with the investigator to understand his/her rationale, and initiate any corrective actions—actions that may ultimately result in removing the patient from the clinical trial. To ensure that the investigator's interpretation is accurate within the constraints of the protocol, the oncology CRA must be able to understand and interpret radiology and lab reports, imaging reports, blood counts, and levels of biomarkers—they are not simply reading the data in the case report, as with other monitoring. This interpretation requires that the CRA possesses complex math skills to calculate exposure to different types of radiation and chemotherapeutic agents. 

Still, this can be a delicate issue to manage if the investigator feels the patient is benefiting from the drug. Ethical issues are often raised, but ultimately the CRA and investigator must follow protocol. Such exchanges require an oncology CRA to be assertive as well as confident in his or her knowledge of the trial's protocol and therapeutic area. 

Another area that requires close attention on the part of the CRA is making sure patients are properly enrolled in the trial—verifying the inclusion/exclusion (I/E) criteria when an investigator enrolls a patient in a study. While CRAs have to do this for all types of studies, knowing the process and performing the complex calculations to determine if a patient is appropriately enrolled is especially challenging in oncology trials given the number and complexity of I/E criteria that must be verified. The patient's charts are often very large, complex, and sometimes incomplete, which makes looking for the data to verify these parameters difficult. Often the I/E criteria require patients to have failed certain drug regimens or to have been exposed to a certain amount of other drugs. Due to complex dosing (such as per body surface area), CRAs must have strong math skills and radiation and chemotherapy knowledge—knowing the current regimens for different cancers. Gaining access to this information, calculating dosages, and verifying the drug exposure is particularly difficult. 

Confident math skills also come into play when performing appropriate calculations to determine the impact of the drug on the tumor size. While it is the physician who makes the determination about whether the cancer is in remission or progression, the CRA must be able to verify the doctor's assessment and discuss any deviations—another checks and balances role. 

While experience will vary from person to person, a clinical background (e.g., in nursing or pharmacy) is preferred for oncology CRAs. An oncology certified nurse (OCN) is often considered the best person to train for a CRA position because he or she already has the clinical and technical background and will only need to learn the regulatory aspects of the role. 

Perhaps one of the most challenging aspects of oncology trials is that of appropriately enrolling patients. Oncology is a sensitive area because of the serious nature of the disease, and patients and families often want to explore every option possible. Families often pressure nurses and investigators to enroll patients in drug studies whether it is appropriate or not. CRAs must have a "heads-up" personality and well-honed people management skills to withstand possible subsequent pressure from nurses and investigators. It is also necessary for CRAs to build good relationships with clinical research staff, which will enable them to have discussions when complex issues arise. This is where a technical background becomes critical; it gives CRAs the confidence needed to address specific questions regarding the protocol, I/E criteria, reporting processes, and other issues. A good relationship with an investigator also makes it easier for a CRA to train and educate the investigator's staff during long-term studies. 

The length of oncology trials poses another challenge for CRAs in that patients must be studied progressively through the end of their lives. The inevitable negative of losing someone to whom they have become attached may steer some CRAs away from oncology trials. On the other hand, the ideal oncology CRA is one who finds it rewarding to work on a project that may ultimately increase someone's chances of survival. 

Pharmaceutical companies are beginning to understand that utilizing a staffing firm—whose sole focus is finding the right candidate match—is a more efficient and cost-effective way to approach specialized staffing. Choosing the right staffing partner can significantly decrease the number of challenges that pharmaceutical companies face while ensuring the success of oncology trials. Because of the long-term nature of these trials, pharmaceutical companies should choose a provider with strong retention programs, as turnover can put study results at serious risk. Turnover also has a negative impact on investigator relationships and performance because having a new CRA with different styles requires additional time and effort from the clinical site research personnel. Additionally, relationships are difficult to build when new CRAs are introduced into the clinical site. 

While CROs assign their staff to a particular study, staffing firms specifically recruit CRAs with oncology experience who have chosen to monitor a specific trial. This increased level of interest often results in a better work output. When CRAs choose the work that they want to be involved in, they are more dedicated and invested, which results in increased retention and quality of work. 

Combating the national shortage of oncology-trained monitors has become a focus for staffing firms. The ability to locate resources in tough geographic markets or train oncology clinical professionals to become CRAs in those markets is a huge benefit to pharmaceutical companies that staffing firms can provide. Locating qualified individuals in specific geographic markets results in decreased travel to the sites, decreased travel costs, increased CRA retention, and improved response time to investigators' needs. Staffing firms also provide value-added services, such as additional training, professional development, and a high level of oversight to ensure quality performance. 

Key to the success of any oncology trial is the high degree of joint ownership between the staffing provider and the client company. Pharmaceutical companies must define their needs and find a staffing partner that best fits with their corporate culture and has a proven track record of recruiting, hiring, training, and retaining the clinical talent needed for the full life of the project. By working together to ensure accuracy, quality, and protocol adherence, the end result will be a mutually beneficial relationship built on trust. 

1. Centers for Disease Control and Prevention, United States Cancer Statistics: 2002 Incidence and Mortality (CDC, Altanta, GA, 2005). 

2. Datamonitor, "Commercial Insight: Generic Cancer Market—New Legislation and a Wave of Patent Expiries to Transform the Market," 14 February 2006. 

3. Food and Drug Administration, FDA Improvements in Drug Safety Monitoring (FDA, Rockville, MD, 15 February 2006). 

 is associate director of clinical operations with Kforce Clinical Research, a division of Kforce Inc., 15260 Ventura Boulevard, Suite 980, Sherman Oaks, CA 91403, email: 

Teaming up with a staffing partner can help companies find the right CRA for their trial.

Skill-Specific Staffing to Ensure Oncology Trial Success

Open-label extension (OLE) studies are common, but they do not receive as much attention as traditional Phase I through Phase IV studies. Enrollment into an OLE study typically follows enrollment into a randomized, blinded, well-controlled main study. Participants are usually informed at the time they are recruited into the main study that they may elect to enroll in an OLE study after completing the main trial. The stated objective of most OLE studies is to obtain long-term safety and tolerability data. 

The use of OLE studies raises some important issues, which until recently have not been discussed. Articles by Wainwright

Data collected as part of a clinical study are used in analyses that address the objectives of the study. The planned analyses are described in a statistical analysis plan, which includes sections on such topics as sample size, specifically defined endpoints, statistical methodology, specific duration of follow-up (as opposed to "until license approved" as seen in some OLE studies), and criteria for success. These topics are typically not well thought out and are even missing for OLE studies. Taylor

  suspects that these data are infrequently published. 

For OLE studies, it is difficult to envision what analyses would be applicable without a control arm. A summary of the OLE study safety results is not easily interpretable without a comparator group. Even if some unexpected adverse events are seen, an epidemiological case is difficult to make against the active treatment since adverse events reported might be related to the long-term consequences of the disease under investigation, a separate disease or condition, or concomitant therapies rather than the active treatment. 

Judging OLE rates against rates from a registry such as the National Cancer Institute's SEER Program (Surveillance Epidemiology and End Results) is problematic since it is difficult to ensure that the populations are comparable. OLE efficacy data can only be presented descriptively, and comparisons with results from other situations—such as historical controls—are often not appropriate. 

A data monitoring committee (DMC) can assess safety by comparing active arm to control arm in the main study, but it has no such tool for an OLE study. Therefore, safety risks are much harder to detect, despite DMC monitoring. The OLE study is generally longer than the main study, and to save costs participant visits are often less frequent. Thereby, the OLE study may impact safety without adding any useful information. 

Caution should be exercised when combining main study data with OLE study data because the OLE population may differ from the main study population or the intended treatment population. Because entry into the OLE study is optional for the main study participants, there is self-selection bias. Subjects who participated in the main trial for a specific reason or reasons may, consciously or unconsciously, apply very different criteria to the decision to participate in an OLE study. Participants who withdrew consent (or died) during the main study would not be eligible for enrollment in the OLE study. Those who had adverse reactions (more likely in active or active control treatment arms, but also possible in a placebo arm) are less likely to enroll in the OLE study; whereas those who tolerated the treatment and/or had desirable outcomes during the main study are more likely to enroll.  

In summary, the population in the OLE study is not representative of the entry criteria of the main study or the intended patient population. 

Ethical concerns may conflict with the need to maintain blinding in the main study. It is standard practice for the participant (and investigative site and sponsor) to remain blinded to randomized treatment even when the participant is choosing whether to enroll in the OLE study. If, in fact, a participant was randomized to the control arm and had a desirable outcome, it may constitute an unnecessary risk to provide this participant with the open-label treatment. Conversely, if a participant was randomized to the active arm and had a poor result (and perhaps thinks, incorrectly, that they were on the control arm), it is again ethically questionable to allow this participant to enroll in the OLE study. 

Obviously, any solution to this dilemma must not put the interpretation of the main trial results at risk, but a guided method of providing randomization assignment information to the participant before they elect to go into the OLE study would alleviate the risk of tainting the main trial results. One possibility

  is to have recruitment into the OLE study handled by an individual not involved with the main study. That individual could receive access to the participant's randomization assignment at the time of recruitment into the OLE study and discuss this as part of the informed consent process. 

Although advocates for OLE studies emphasize that the OLE will allow all participants—even those initially randomized to the control arm—to receive active treatment, making the OLE study available to all main trial participants could easily be construed as a coercive practice. This could especially occur when this inducement is used as part of the marketing of the study to help recruitment. It is generally agreed that study participants should not receive excessive monetary inducements. For the same reasons, they should not be promised open-label treatment that they would not otherwise be able to obtain or afford. Some study participants may enter the main study for this "carrot" even if participation in the main study was not in their best medical interest. 

It is well known that participants tend to overestimate the potential benefits of a new treatment and minimize its risks. Study organizers should approach a study with equipoise, meaning that they should espouse a reasonable belief that the efficacy of the active treatment could be the same as that of the control treatment, and that there is a potential for additional safety risks in the active treatment. The OLE study should not be used as an enticement for the main study. If a potential participant is eager for access to this new treatment and is therefore more likely to participate in the main study solely because of the opportunity to enroll in the subsequent OLE study, it may be easy and tempting for the clinical site to boost enrollment by silently acquiescing. Instead, sites must proactively and responsibly present the risks, benefits, and unknowns to all participants regardless of the effect on patient enrollment. 

How can one address the need for additional safety data? The point is that the only way to obtain proper long-term safety data is to conduct a randomized controlled study of safety. Regulatory agencies should acknowledge this and not simply insist that a certain minimum number of years of patient exposure are required before approval. Instead, patient exposure should be meaningfully collected and analyzed. 

If there is compelling evidence from earlier studies that the active treatment has superior efficacy and the decision is made that long-term safety data are needed, then at a minimum the OLE study should be an entirely separate Phase IV study. The control arm in such a study might not ethically be a placebo arm, but it could be an arm receiving the "standard of care," if one exists. The presence of a "standard of care" treatment arm could be critical, so potential study participants would be guaranteed some efficacious treatment, and the results would be interpretable by comparisons of the active therapy arm to the "standard of care" arm. 

Such a well-controlled safety study does not have to cost that much more than an OLE study, as both types would potentially last for years. A well-controlled safety study would provide much more useful information than an OLE study and, in the long run, could not only protect study participants and potential consumers, but also the financial interests of the sponsor.  

If excess risk truly exists, it will hopefully be detected earlier rather than later, after millions of patients have been treated, which potentially could result in a disastrous deluge of litigation. And if the risk is not excessive, a well-controlled safety study is powerful evidence to refute accusations based on anecdotal evidence or on inappropriate comparisons with historic information. 

Many of the previous comments apply as well to a variant of the OLE study in which participants experiencing negative outcomes during the main study (e.g., a relapse or flare, disease progression, or a certain minimum change in outcome score) are immediately placed on open-label active treatment. This practice may be even more problematic than the OLE studies described, since it can seriously affect the interpretability of the main study. 

A comparison of active treatment to control treatment at a specific final visit will be confounded because some participants randomized to control treatment receive active treatment. In essence, the active treatment will be compared against itself. So a potential treatment effect will be muted by these crossover subjects in this OLE variant. 

Some studies in this case attempt to reconcile this difficulty by automatically assigning a result of "failure" for these subjects who cross into the open-label extension. This is only appropriate for a time-to-event analysis, where the question then answered is whether time to first negative result is delayed by the active treatment. In such a case, the criteria for switching to open-label treatment should be clearly delineated and be clinically relevant. 

Such an imputation of "failure" would be inappropriate if the study was designed to evaluate outcome at some specific protocol-specified final visit. The negative outcome seen during the course of the main study could well be transitory with the participant having a positive outcome at the specific final visit. 

If the primary endpoint is status at a specific final visit and some rescue treatment is truly deemed necessary in the case of a negative outcome before that time, then the participant should be offered "standard of care" rather than open-label active treatment. A potentially useful comparison is achieved: "active treatment plus ancillary standard of care" versus "control treatment plus ancillary standard of care." 

In summary, OLE studies, despite being a standard addition to many well-controlled studies, need to be examined much more carefully to determine whether they are statistically meaningful and ethical. If OLE studies do not provide clinical insight or (more cynically) are done simply to get clinical sites accustomed to providing the new treatment in anticipation of regulatory approval, then this clearly is a problem that needs to be addressed. 

1. P. Wainwright, "Consent to Open Label Extension Studies: Some Ethical Issues, 

2. G.J. Taylor and P. Wainwright, "Open Label Extension Studies: Research or Marketing?" 

 MS, is a biostatistician and project director with Axio Research, 2601 4th Avenue, Suite 200, Seattle, WA 98121, (206) 547-2829, email: 

Open-label extension (OLE) studies are common, but they do not receive as much attention as traditional Phase I through Phase IV studies. Enrollment into an OLE study typically follows enrollment into a randomized, blinded, well-controlled main study. Participants are usually informed at the time they are recruited into the main study that they may elect to enroll in an OLE study after completing the main trial. The stated objective of most OLE studies is to obtain long-term safety and tolerability data.

Spotlight on Open-Label Extension Studies

For all clinical trials, it is necessary to perform drug accountability, reconciliation, returns, and destruction (ARRD) activities as part of managing the complete drug supply chain. The strict regulatory stance on this area places the onus on biopharmaceutical companies to ensure this process is followed diligently. However, the reality of conducting and fulfilling this requirement can often prove extremely difficult and time consuming for study personnel. 

The challenge of ARRD in a clinical trial is that full documentation of the chain of custody for study material from bulk manufacture to eventual collection and destruction must be available, and the sponsor is held responsible for providing the full evidence of this including any changes to the relevant documentation. However, audit findings (both internal and regulatory) indicate that current ARRD processes do not always provide this level of information in a clear and concise way at study, site, and/or country level. 

Drug accountability and reconciliation are painful activities for site and monitor personnel. The current largely paper-based practices mean dealing with disparate and duplicate data sources, making it a highly labor-intensive and time-consuming process. This also makes it difficult to demonstrate the complete chain of custody information for medication units. This article will address the regulatory requirements for a sponsor to produce documentation of its drug accountability, the problems of current processes, and the way forward for the industry. 

When studying the problems associated with ARRD, the overall process flow that biopharmaceutical companies are required to follow must be considered. In order to understand the process itself, it is essential to recognize all four components of accountability, reconciliation, returns, and destruction. Although there remains some degree of variability between sponsors, study protocols, and country practices, the high-level description of the typical process is the same. 

The fundamental goal of drug accountability is to know at all times the exact status and location of all medications throughout the entire supply chain. The ARRD process should effectively begin with the manufacture of the study drug. This process then follows the drug's entire lifecycle through packaging, shipment, dispensation, return, reconciliation, and, ultimately, destruction. Existing processes at manufacturing sites mean that this element of ARRD is highly visible, as this is within the sponsor's direct control. However, once the drugs are shipped, the process becomes much more difficult to manage as information starts to appear in a number of formats from different sources, as detailed in Figure 1. 

 Figure 1. Keeping track of a drug status from packaging to destruction is the essence of drug accountability.   			

In general, investigative sites are required to maintain an inventory of supplies received and returned—a "master supplies log" and a "subject dispensation log" to record individual medication given to and returned by each patient (see Figure 2). These two documents are typically the key informational repositories of site-based drug accountability, although additional sponsor and/or site specific documentation may also be used. Subject returns may be captured simply as the return of the pack dispensed, or more frequently, by capturing the quantity of medication returned. 

Figure 2. Investigative sites must maintain a master supplies log and a subject dispensation log to record individual medication given to and returned by each patient.			

The next step of drug reconciliation is typically performed by a monitor who verifies and reconciles all of the received, utilized, and recovered medication for each site according to the sponsor's written procedures. This entails checking the site documentation and physically verifying quantities and status of all relevant materials. Additionally, monitors will often coordinate the return of drugs from the site to an appropriate destination, which in most cases is a local depot. This may include other supplies that are no longer useable or necessary, such as damaged or expired medication. 

Next, return shipments are sent to a designated depot accompanied by a document detailing quantities, individual contents, and format of medication. A unique identifier is assigned to each shipment, and very often this is the only tracking device to link the shipment received at the depot with the individual medication packs sent from the site. 

Figure 3. Electronic ARRD would automate current paper-based dispensation, return, and destruction of medication supplies. This would afford trial professionals complete control of the supply cycle. 			

Upon receipt of a returns consignment, the depot must clearly identify the supplies, store them in an appropriately controlled area, and maintain inventory records. In approximately 20% of cases, the depot is required by sponsors to undertake a further reconciliation activity verifying received contents matched against those shown in the shipment documentation. 

Finally, the returned materials must be destroyed.  Returned supplies are generally stored at the depot until enough have accumulated to warrant sending a large shipment to the final destruction facility. At destruction, a certificate must be issued, and the study sponsor must link the information back to the individual medication units to prove both the identities and quantities of destroyed material. 

Throughout the entire process, if any discrepancies are identified they must be investigated, explained, and resolved. 

Good manufacturing/clinical and distribution practices mandate that ARRD procedures must be implemented in all investigational clinical trials. There are both European

  regulations that sponsors need to take into consideration at the inception of every study. 

According to the European Commission's Good Manufacturing practices guide Annex 13

"The delivered, used and recovered quantities of product should be recorded, reconciled and verified by or on behalf of the sponsor for each trial site and each trial period. Destruction of unused investigational medicinal products should be carried out for a given trial site or given trial period only after any discrepancies have been investigated and satisfactorily explained and the reconciliation has been accepted. Recording of destruction operations should be carried out in such a manner that all operations may be accounted for." 

  also state that the investigator is responsible for the proper and secure physical storage and recordkeeping of investigational agents. More specifically, the regulations state that the investigator must: 					

Maintain a careful record of the receipt, use, and final disposition of all investigational agents received using the Drug Accountability Record Form

Store the agent in a secure location, accessible to only authorized personnel, preferably in the pharmacy

Maintain appropriate storage of the investigational agent to ensure the stability and integrity of the agent

Return any unused investigational agents at the completion of the study or upon notification that an agent is being withdrawn.

The intent of these drug accountability procedures is to assist the investigator in making certain that drugs are used only for patients enrolled in an approved protocol. 

Regulatory bodies conduct audits for various reasons but always ultimately to ensure the safety of research participants and to guarantee the accuracy and integrity of the clinical data collected. Clinical Investigators are well aware of the possible consequences of a negative regulatory inspection. At worst, this might result in disqualification from research and possible jail sentencing. More likely, disciplinary actions range from a figurative slap on the wrist to restrictions that limit participation in future projects.

  The FDA Web site lists many warning letters specifically mentioning drug accountability violations.

  These letters include warnings on aspects such as incomplete or inaccurate dispensing records, failure to maintain adequate drug inventory, and the unavailability of drug distribution records. Many of these issues could have been prevented by proper drug accountability procedures and regular checks during monitoring visits. 

While many clinical processes are progressing into the electronic age in an effort to make them faster, more efficient, and more accurate, the ARRD process has lagged behind. Most clinical sponsors address the ARRD regulations by relying heavily on inefficient manual paper-based systems with information coming from a number of sources in a variety of formats including, for example, electronic shipment files, emails, paper forms, and handwritten notes. This paper-based process makes it difficult to access information detailing the complete chain of custody for individual units of medication through a trial's lifecycle. Aggregate-level transparency frequently—particularly study or batch-level—is very poor, making it extremely difficult to obtain a holistic snapshot of the overall supply status. Mistakes are common due to multiple locations and formats of the same data, leaving studies vulnerable to audit findings. 

Accountability and reconciliation are viewed as the most difficult aspects of the ARRD process to maintain, and this could be facilitated by an electronic solution to track and reconcile materials throughout their entire lifecycle. For example, Michael Grabo, PhD, F. Hoffman-La Roche Ltd., Pharmaceutical Division, Pharmaceutical Development Operations, states:  

"Drug accountability and reconciliation are painful activities where the site and monitoring personnel really bear the brunt of the manual process. The largely paper-based documentation which is often disparate and duplicate means people spend many frustrating hours accounting for and reconciling investigational drugs throughout the duration of the trial. As we are continuously trying to find ways to work smarter and more efficiently, this is clearly an area that will benefit enormously from an electronic solution." 

Certain electronic solutions can assist with aspects of the ARRD process. For example, interactive voice and Web response (IVR/IWR) systems are already used to control the distribution of drug from depot to site and allocation to a subject.

  Some clinical trial management systems (CTMS) and drug supply management systems (DSMS) provide the ability to track certain elements of drug accountability. However, key stakeholders, such as site and depot personnel, rarely enter information directly into CTMS or DSMS databases—so these systems serve as a second record of data currently recorded elsewhere and do not make drug accountability quicker or more reliable. 

IVR/IWR medication management solutions provide full control of one direction of the clinical supply chain—from central storage depot to subject allocation.

  An electronic ARRD solution would, therefore, be a logical extension—taking into account the remaining steps of recording the physical dispensation to subjects, receipt of their returned supplies, return of used/unusable medication held at site to appropriate depots, and the ultimate destruction of supplies (Figure 3). Because current users of IVR/IWR solutions include study site personnel, site pharmacists, monitors, and depot personnel, extension of these solutions provides a real opportunity to eliminate or limit the paper-based activities and centrally provide complete visibility of the entire ARRD process. This would provide sponsors with total custodial control and traceability of the entire supply chain from manufacturing to destruction. 

The desirable properties of an electronic solution for ARRD are detailed below. 			

Real-time data visibility, reporting, and error-checking

. An electronic system should allow sponsor personnel to have instant access to supply information and be capable of reporting summary-level, aggregate information based on a wide range of variables as well as granular, custodial tracking of individual medication units from creation to destruction. An ARRD solution must also incorporate edit checks to limit any unnecessary errors and provide functionality to flag and manage the resolution of reconciliation discrepancies. Enabling the user to provide reasons for discrepancies found would be an essential property. 

 A solution should complement the working practices and processes followed by the end-users.  Solutions should provide an easy-to-use environment with no  limitations. A Web-based application is likely to enable most of the functionality requirements, but should be designed with end-user performance and convenience in mind. 

. Monitors should be able to perform their activities at sites with and without direct connection to the application. At some sites, obtaining access to the Web may be problematic; so the application must be able to enable CRAs to undergo their activities while limiting the requirement to rekey data when in the office. Many modern CTMS solutions include offline working for monitors, and this type of functionality would be attractive for an ARRD solution. 

Integration with other eClinical solutions

. Integration with other eClinical solutions is important to prevent duplication of data and activities. Integrations that might prove valuable for an ARRD solution would include those with IVR/IWR systems, CTMS, and DSMS applications.  

. An electronic ARRD system could create a complete and compliant audit trail that can be maintained throughout the return cycle. Like an EDC solution, it will be vital to accurately authenticate each user and to record the user, time, and date against all entries made. The ability to change data should require documented reason for change, with previous records retained within the audit trail.  Access rights will be important to ensure specific user-types retain responsibility for key activities. 

Using an electronic ARRD solution to reconcile and track the destruction of unused clinical materials provides numerous benefits including full visibility of chain of custody for investigational and medicinal products, centralized management of processes, and reduction in paperwork and errors. In combination with IVR/IWR this allows sponsors to implement an integrated IT approach from the decision to begin a study through enrollment and randomization of the first patient, right through to the destruction of the last drug unit. 

1. European Commission Enterprise Directorate-General, Annex 13: Manufacture of Investigational Medicinal Products (EC, Brussels, July 2003). 

2. Food and Drug Administration, 21 CFR 312 Investigational New Drug Application (FDA, Rockville, MD, April 2005). 

3. Food and Drug Administration, 21 CFR 211 Current Good Manufacturing Practice for Finished Pharmaceuticals (FDA, Rockville, MD, April 2003). 

4. Food and Drug Administration, 21 CFR 210 Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs (FDA, Rockville, MD, April 2005). 

Electronic solutions can enhance the efficiency of tracking drugs throughout a clinical trial.

Managing the Drug Supply Chain with eProcesses

Software digitizes the entire clinical trial source and lifecycle management process

(Austin, TX) is offering a twist to traditional clinical data management software packages. Its InterRx platform integrates all source data, along with data capture and trial operational metrics, into the digital trial management solution. This saves users the time and trouble of keeping secondary systems to monitor the trial's operational and clinical effectiveness, says the manufacturer. 

InterRx is a versatile tool with diverse utilization opportunities. It can serve as a hosted digital trial research or management solution for decentralized sites, or as part of a rapid deployment CRO solution. The platform enables rapid protocol implementation, trial and data management, patient safety, team communications, real-time trending analytics site efficiency, enrollments, and FDA submission preparation. 

Its manufacturer says InterRx reduces study start times 60%–70% on average. The suite of InterRx packages includes InterRx Data Manager, InterRx LifeCycle, and InterRx CRO. 

Precerche Life Sciences, LP, (512) 233-0197, 

Server-connected dispensing bottle puts a new spin on automated patient compliance 

(Acton, MA) has a fail-safe patient compliance technology that relies on an everyday tool: cell phones. The SIMpill Medical Compliance System consists of a pill bottle that is connected to a module with cell phone components. When a patient opens the cap on the pill bottle, an SMS message is sent via a wireless network to a secure central server that documents the event. If the server does not detect a cap removal by a certain time, it sends a message to a designated caregiver's cell phone. If this does not prompt the patient to remove the bottle cap, a follow-up message is sent 15 minutes later. 

The dispenser's manufacturer, UK-based SIMpill (Pty.) Ltd, says GSM networks reduce reliance on physical networks, making the device more widely usable in developing communities. Trial monitors can verify compliance in real time via the Web-based interface feature. Data on compliance levels measured by the device are stored for future analysis. 

Clinical Technology Advisors, (978) 263-9596, 

Latest release promises to further expand open source software's interoperability prowess    

(Cambridge, MA) is adding new interoperability features to its OpenClinica open source, Web-based software platform, designed to enable sponsors and investigators manage clinical research data in multisite studies. Highlights of the suite's new capabilities include enhanced EDC and data management, new tools for study coordinators and monitors to conduct source data reviews, and data output in SAS and CDISC XML format. 

Also notable is OpenClinica's improved data persistence layer, which enables compatibility with the NIH caBIG project, facilitating research in the cancer arena. This version, which is undergoing beta testing, will also feature compatibility between electronic data collection instrument and CRF metadata models. This feature will support a platform-independent CRF definition through HL7v3-compliant XML-based messaging. 

eShowcase

For an industry that's normally held in fairly high regard in most countries, how on earth did the pharma industry develop such an image problem in the United States? According to the annual Harris Interactive poll, Americans now lump the industry in the same category as oil companies, tobacco companies, and health insurers when it comes to trust and honesty. 

Saying that the industry "has a public relations problem" suggests that all it will take to fix the problem is some well-crafted messages, a bunch of ads, some feel-good activities, and a series of public appearances. However, the problem lies much deeper and is at the heart of what public relations is all about: building a relationship with the people most important to your success. Poor relationships make it harder to do business, while strong relationships, on the other hand, usually make it easier. 

The industry's problem has its roots in how it constructed the architecture of its relationships as it grew. Almost from the start, it showed a complete lack of understanding of the critical stakeholders it needed to build a relationship with: the end user, its customers. Time and again, the industry "missed the boat" with consumers, becoming estranged from the very people so critical to its own well-being and success. 

Certainly the industry learned during its formative years in the 1940s and 1950s that it needed to build a relationship with the health care professionals who prescribed pharma products. But this symbiotic relationship shut out the patient from information and knowledge—except for the information they could wheedle out of their doctor or pharmacist. Relying on these learned intermediaries, the patients also had little idea who made the drugs they received. It's hard to build trust when you have no idea who you're building it with. 

As the industry became larger, it came under increased public scrutiny, which started in the 1960s with the thalidomide crisis. By the time pricing and access issues began pelting the industry in the 1980s, the industry had developed relationships with legislators, regulators, and Wall Street. These relationships helped fend off legislation on pricing control during the Clinton Administration—but the industry still did not have a direct relationship with consumers. 

Today, despite the stunning medical advances the industry has made and the life-saving and life-enhancing role it plays in the lives of millions of people, it is really not much closer to the kind of intimate and personal relationship with our parents, children, neighbors, and friends than it was 50 years ago. While there is certainly much more work going on to develop these relationships, the industry does not have enough capital in its "trust bank" to help it weather the storms washing over it. 

Right now the industry has a chance to reclaim its good name and recapture the public's respect for the power of what it can do.

Applied Clinical Trials-07-01-2006