Over the past 15 years, methodology and ethics have become important issues in the design and conduct of multicenter clinical trials. Nowadays, clinical research embraces very different disciplines, such as information technology, regulatory affairs, quality assurance, and economics, and it is associated with a complex regulatory framework. The recent EU Clinical Trials Directive has added even more to this complex framework. All of this makes clinical research a more complicated process, and this translates into a difficult planning phase, increased trial time, increased costs, and additional energy.

Generally, the start up of a clinical trial requires a new design, and once the trial is completed the entire process used in the design is discarded. There is no system currently available that can manage the activities of clinical trials based on the interoperability of each single task. A detailed model of the entire CT process would allow for controlling the process in all its phases, in particular: 					

Writing the protocol coherently and consistently so that it supports the collaborative work of the writing committee members 

Facilitating and coordinating the setup of the trial in the various participating centers

Supporting the critical phases of the process, such as the eligibility, drug supply, severe adverse events (SAE), etc.

Monitoring the setup, particularly the quality of clinical data and timely collection of case report forms (CRFs)

Supporting the evaluation and diffusion of clinical trial results.

There appears to be a strong demand for integrating research and systems in a way that supports the whole clinical trial process.

  Such an approach can foster interoperability between CT software applications, making system reengineering and maintenance easier. For this reason, we propose a clinical trial model that provides a more detailed analysis of the entire CT process to better understand the number of procedures carried out during the trial.

  Our approach is based on a holistic view of CTs. We are developing a comprehensive conceptual model of the CT process independent of the possible information and communication technology (ICT) solutions applied to the process automation. 

 Figure 1. Process types in the clinical trial process.			

In order to develop a standard model and a common terminology, GIMEMA (The Italian Group for Haematological Diseases of Adults) together with the Italian CNR (National Research Council) have developed the first version of a detailed model of the entire CT process that focuses attention on:  					

data needed to synchronize CT activities carried out by the different actors involved (e.g., sponsor, investigators, data managers).

From the analysis of this model, it will be possible to: 					

verify the pillars of the trial and, thus, identify the different types of support that ICT can offer in this field (e.g., applications for communication between and within centers, CRF and serious adverse event (SAE) management, and tools for execution monitoring)

help and support the writing of a consistent protocol that describes the entire process in a detailed, comprehensive, and coherent way for all actors involved in the performance of the trial

determine which parts of the process are independent from the type of trial and which ones vary, thus helping to achieve a standardized protocol text.

We propose to model trials as a highly organized process that is composed of subprocesses.

  We have identified three main subprocesses. Each subprocess has different objectives and is enacted in different environments, carried out by its own agents, supplied with needed resources, and governed by specific rules. The three main subprocesses are: 									

The clinical trial management process (CTMP), which includes activities related to the setup, coordination, and monitoring of the CT participating centers, and the final evaluation of trial results. This process is carried out by the sponsor. 

The statistical units management process (SUMP), which includes activities related to the management of the trial in the participating centers. In our approach to trials, a statistical unit indicates an instance of an enrolled patient. The process described in the protocol is executed in each center and performed on each enrolled patient. 

The patient health care delivery management process (PM), which relates to the diagnostic and therapeutic activities necessary to treat an enrolled patient, following the instructions defined in the protocol. This process is carried out within the clinical ward (CW).

Figure 1 describes the relationship between the three process types. As soon as the clinical protocol is developed by the writing committee and approved by the scientific and ethics committees, the sponsor opens participating centers to enrollment. This is why in the figure the CTMP triggers the SUMP for each participating center. In each center environment, for each enrolled patient a PM process instance is created. This means that at a certain point in the SUMP there are as many PM instances as the number of enrolled patients in treatment. For the SUMP, these instances represent statistical units that will be evaluated during the analysis of the clinical trial results. 

Figure 2. Data flow of the clinical trial.			

In our approach, modeling a process means to identify the main participants involved, the needs of participants with regard to what procedures need to be carried out, the objects used (resources) and delivered (results) by the process, and the rules that constrain the execution process. Generally, two processes may be synchronized on certain events or objects: One process (the consumer) will not start because it has to wait for an event or object produced by the other process (the producer). Some of the subprocesses are simultaneous and their interaction may be triggered when specific clauses/conditions are produced because of the occurrence of certain information/documents or specific events. 

Figure 2 shows the information flow between the trial processes and specifies the different types of information exchanged (e.g., data, resources, commands/directives, workflows/process specifications, etc.). This information is contained in at least one of the following three highly structured documents: 					

The CT master file. This file contains the information necessary to set up and perform the entire CT. The whole CT process can be divided into three sequential macro phases: preparatory, execution, and evaluation. In the preparatory phase (which is represented by the CTMP in Figure 1), the focus is on planning and specifying what needs to be done in the following phases. In the first phase, one of the main tasks is the development of a CT master file. The CT master file contains, among other documents, the protocol (i.e., the document that describes the trial's objective(s), design, methodology, statistical considerations, and organization) and the CRF templates (i.e., a document designed to record all of the protocol required information to be reported to the sponsor on each trial subject). After defining the contents of the CT master file, two processes can start: database creation and writing of the operating procedures manual. The start-up experimentation process can begin only when the previous three processes are concluded. 

The CRF database gathers the CRF from all patients. A compiled single CRF form describes the patient's health status in each well-defined phase of the CT execution; the whole CRF also reports the changes in the patient's health status occurring during the CT. Analyzing the type and number of compiled CRF forms makes it possible to monitor the CT execution.   

 The HCR is the official repository of the clinical information related to a patient in a given CW. It contains both the information on the therapeutic approach and changes in the patient's health status. Data needed to fill in the CRF are extracted from the HCR, and the quality of the CRF data is verified through the HCR.  

The model is defined by a formal language (UML), which describes the process from three different points of view: functional, structural, and behavioral.

  Each view highlights a specific aspect of the trial (e.g., the flow of activities, the data structures, and the interaction between the various activities involved in the process). 

We used the model to outline areas where ICT can improve and optimize the whole process. In particular, the model has been used to: 					

Design an information system, which helps the protocol writing and guarantees its completeness and coherence as well as the extraction of information necessary to automate single activities of the trial

Formalize the rules that govern the exchange of data in the CT process, which enables interoperability between the various ICT systems managing the single activities of the process

Define a procedure that guarantees the quality of the CT process related to all its activities.

The protocol is a planning document for the whole CT, where all activities of the process are taken into account. The functional view of our model is an excellent guide to protocol development. This view also includes data necessary to perform each single activity in the CT process, which has allowed us to define a structural framework that guides the text editing and controls its consistency. The framework has been specified by an XML scheme, which facilitates search functionalities within a database of protocols, re-use of single parts contained in the text, and interoperability with other systems.  

We implemented a system, WITH (Write on Internet clinical Trials in Haematology) that helps the CT writing committee monitor the different phases of the writing process, re-use parts/sections already written belonging to previously developed protocols, and promote the text coherence obtained through the management of XML tags as well as a related data dictionary. 

Another important aspect of the process, which has been emphasized by the model, is the exchange of information between various activities. The structural view of the model allowed us to define an XML format of the exchanged messages, guaranteeing the interoperability between the parts of the system. In our case, the achievement of interoperability also makes it possible to develop and test autonomously single modules of the system, which can be gradually implemented and easily updated to standards such as HL7 (Health Level 7) and the CDISC Operational Data Model.

  The use of standards guarantees the provision of seamless and automatic connections from one software to another, regardless of platforms, applications, or programming languages. 

Since our model provides a reference framework for all CTs, it can help achieve the uniformity of protocol quality evaluation. Moreover, having a controlled system that governs all single steps regarding the conduction of a given trial can guarantee that the main regulatory issues are respected. As a result, a standard good practice can be developed that guides the stakeholders (physicians, investigators, sponsors, etc.) during the CT process. 

The process model we are studying is the starting point for defining standards related to the use of ICT in CTs. In fact, this model identifies how data (messages) between the various activities should be exchanged. These messages need to be standardized in order to achieve semantic interoperability for the automation of the entire clinical research process. At a higher level, the CT model enables organizational interoperability by defining a virtual community of organizations playing roles as CT coordinator, participant center, etc. 

 MD, are with the The Italian Group for Haematological Diseases of Adults (GIMEMA), Dip. di Biotechnologie Cellurali ed Ematologia, Universita degli Studi di Roma "La Sapienza," Via Benevento, 6, 00161 Rome, Italy, +(39) 06 441 639 828, fax +(39) 06 440 2516 639 828, email: 

 is a researcher with The Italian National Research Council (IRPPS-CNR), Rome, Italy. 

 is a professor with UPB - "Politehnica" (University of Bucharest), Bucharest, Romania.

Articles

Feature Article

This new model standardizes data exchange between the various stages of a research study.

A Proposed Clinical Trial Model: Analyzing the CT Process

Several years ago, authors Radhika Bobba and Yamin Khan analyzed the advantages and disadvantages of using India as a preferred location for clinical trials (CT). The article in 

 prompted Neermen Varawalla to comment that there were still many hurdles facing international companies who were willing to consider using India as part of their global clinical development resources. She said that "unless the tacit concerns of the global pharmaceutical industry are effectively addressed, the opportunities in India will remain underused." 

The advantages of running trials in India are well-known (large naïve population, plethora of highly skilled, English-speaking health-care professionals, lower costs, etc.). More interesting, however, is the discussion of the obstacles as perceived in 2003 (quality and acceptability of the data, ethics, bureaucracy, lack of patent protection, etc.) and what has been done since to address these issues. 

Since 2003, several Indian companies have moved from simply manufacturing generics to becoming world-class R&D companies whose objectives are to develop innovative drugs for the global market. These local companies therefore share the needs of foreign firms to operate under a properly regulated environment, and to develop a competent and well-trained workforce.  

Concerns about data validity and acceptability were mostly due to lack of ICH-GCP-trained clinical research staff. There are now numerous public and private organizations, such as the Institute of Clinical Research of India, which propose a one-year degree for aspiring CT professionals. The same can be said about quality assurance with the development of QA firms, both local and international.  

The debate on ethics paradoxically has become more troublesome. With increased public awareness of CT activities, the debate has become more political, and one now hears more voices within and outside India criticizing the use of "poor and uneducated Indians as guinea pigs by the International Pharmaceutical industry." Not only is this affirmation false, but it can lead to the exclusion of the Indian population from the benefit of new drug development, and that is unethical. In the recent past, India did lack proper government control of CT activities. This is now being addressed by the Indian Government through the introduction of measures institutionalizing control of CTs in India. 

One of the most difficult issues at this time is the increasing negative publicity that the pharma industry in general, and multinationals in particular, receive in India and abroad. In November 2004, the leading Indian biotech journal, 

, published an article titled "Clinical Trial in the Eye of a Storm." The article analyzed all the incidents that recently undermined public confidence, such as misuse of an NGO to divert trade secrets, conducting clinical trials without authorization, and falsifying consent forms. These issues are not specific to India, and there is no data supporting the view that such incidents occur in India more frequently than elsewhere.  

India's bureaucracy is often mentioned as an obstacle. I would argue that requirements by Indian authorities for performing CTs are no more than what FDA or EMEA requires. The problem is only a lack of knowledge by foreign companies of what is required. This is now being addressed by the development of numerous highly competent consultancies and CROs in India who can help foreign companies to better understand the requirements. 

Last but not least, the most frequently mentioned problem used to be the lack of patent protection. However, after a protracted debate, the Indian Parliament finally passed the Patent Protection Act in March 2005. This provides protection for patents registered after 1995, while maintaining the rights of local companies. This effectively removes the threat of having generic copies on the Indian market even before the parent drug is approved anywhere else. 

India today retains all of its attraction, including an immense reservoir of patients and doctors, and most obstacles have been removed. Patent protection, training centers, and government control have now been put in place, and nothing should stop companies from considering India for their next global drug development program. 

When I visited Bangalore last year, I met a 30-year-old Indian man with a PhD from Stanford who had been working for nine years in California. When I asked him why he had come back to take up a managerial position in Bangalore in a leading CRO, his answer was: "Better getting the good jobs here while they are available, rather than wait there for my position to be outsourced to Bangalore." Smart guy!  

A Closing Thought

Closing Thoughts on the state of clinical trials in India today.

India: Have We Made Progress?

SAS offers a single platform for life sciences companies, eliminating integration headaches.

Say you're a typical life sciences company using a different point solution for each of your departments. This hybrid approach has not always been the best for the research and development process as a whole, since your organization must eventually spend valuable time and resources integrating these solutions. 

 (Cary, NC) has teamed up with CRO Constella Group, Inc., EDC software vendor DATATRAK, and eClinical software vendor etrials Worldwide to form Life Sciences Network Powered by SAS. Through the program SAS plans to work with selected vendors, CROs, and service providers to offer easier application integration to LS companies. 

The network relieves organizations from the toils of IT integration by offering hosted and enterprise applications under one umbrella—a single platform for integrated solutions in key areas such as e-capture, patient diary systems, IVR systems, collection and reporting of lab results, safety and medical coding, as well as postapproval studies and registries.  

www.sas.com/industry/pharma/develop/lsn.html

Clinical labs with smaller volume requirements have a workstation that fits their needs—and budgets.

, a division of Magellan Biosciences (Chelmsford, MA), has introduced a clinical diagnostic and biomedical research workstation within the reach of near-patient laboratories and other clinical labs with smaller volume requirements. The DS2™ System is a fully automated clinical diagnostic workstation designed to capture more accurate, immediate clinical diagnostic results at a lower cost than with full-fledged diagnostic systems. 

Designed for lower-throughput clinical labs, the DS2™ System features advanced automation and precise liquid-handling capabilities to eliminate variations common in manual processes. This allows clinicians to obtain accurate immunology to infectious disease analyses, hormone allergy, blood chemistry, etc. The workstation can process two 96-well microplates and up to 12 different assays simultaneously. It performs the entire complement of analytical steps needed for virtually any ELISA immunoassay, plus it has an advanced, user-friendly control system. 

FDA partners with GlobalSubmit to deal with the expected deluge of eCTD submissions. 

 The FDA needed a robust electronic solution for handling the large number of anticipated Electronic Common Technical Document (eCTD) submissions. Enter 

 (Haddon Township, NJ) FDAreview software for reviewing eCTDs. 

Under a partnership arrangement, the FDA and GlobalSubmit will collaborate on the deployment and enhancement of FDAreview, which replaces the FDA's Electronic Common Technical Document (eCTD) Viewing System (EVS).

In the coming years, the FDA anticipates that a large number of pharmaceutical companies will submit documents using eCTD technologies, affording FDA reviewers quicker access to key information. The payoff for sponsors will be time and cost savings during the drug development process and during the preparation of documents for submission to regulators.  

eShowcase

In the coming three years, the market for electronic data capture (EDC) and electronic patient reported outcomes (ePRO) technologies is expected to grow faster than its historical 23% annual rate. Several key factors are expected to drive adoption, including growing regulatory and organizational support for data interchange standards; continued market consolidation; improved availability of investment capital; and improved vendor functionality and performance. Engaging sites as more active partners in EDC decisions and providing more responsive technical support should also be recognized as a critical adoption driver. 

A few years ago, investigative sites were almost unanimously frustrated by the unmet promises of technology solutions. Today, sites are far more receptive to EDC and ePRO, but many feel that they are entering into a commitment to adopt these solutions without the full and necessary backing of research sponsors. Sites are particularly concerned about the variability in technical support availability and responsiveness, the lack of compatibility between sponsor data collection systems, and the failure of sponsors to inform sites that eClinical technologies will be used at the outset of an engagement. As a result, many investigative sites are reluctantly and cautiously adopting eClinical technology solutions, often relying on paper-based approaches as an insurance policy against inevitable problems. 

A recent survey conducted by the Clinical Data Interchange Standards Consortium (CDISC) among 150 North American clinical investigators and study coordinators finds that most investigative sites are preparing themselves for the electronic age of clinical trial conduct. Almost all sites report having dedicated staff now trained on electronic case report form (eCRF) and ePRO systems. More than half of sites report having developed standard operating procedures (SOPs) specific to eClinical trials. 

But technical support, particularly for ePRO systems, is one of the largest aggravations for investigative sites. According to the CDISC survey, most investigative sites want to see more responsive technical support. More than half of investigative sites report specifically having technical challenges with ePRO technologies, most notably among their elderly study volunteers. Investigative sites typically must turn to the study coordinator for help—an individual who is often the least equipped to troubleshoot problems. Some sites report that even when an actual help desk has been established, it often is unable to troubleshoot as well. 

"At an investigator or initiation meeting, the coordinator typically receives cursory training on the equipment, but of course cannot function as a help desk," said one site director at a research center based in Salt Lake City, Utah. "One recent study was a total disaster," she said. "Participants had palm pilots they entered data into and downloaded daily. But the devices didn't work consistently, the phone number to call for downloads didn't function properly, and it was extremely difficult to get answers from the help desk based in another country. Unfortunately, the participants associated the problems more with my site than with the sponsor company." 

"Sites really need not only better training, but also written instructions to give participants when ePRO is being used and a protocol-trained help desk with 24/7 availability," suggested a study coordinator at a site based in the New York area. 

"We find that some help desks are always available, but never helpful when it comes to anything protocol specific," said a Cincinnati-based site manager. "And the sponsor is rarely ever helpful when answering technical questions. Most questions have a technical component as well as a protocol specific component. That means the site may have to contact multiple people to get one question answered." 

The fallout from inadequate technical support is a time delay for the research sponsor and lost time and revenue for the investigative site. "If study participants can't get the data downloaded that continues to qualify them for a study, they may quit or they may be dropped from the study," commented a study coordinator. 

Investigative sites remain adamant that sponsors should collaborate to better standardize data collection systems, if only to reduce the mounting number of incompatible desktop and laptop terminals. The CDISC survey found that the typical investigative site has an average of three disparate systems to capture transcribed CRF data. Complicating the issue is that many sponsors have fashioned their own proprietary EDC systems that require unique training and support. With increasing turnover among study coordinators, investigators and site managers often face the challenge of having to rapidly train new staff to stay on top of electronic data collection activity. 

"We've got more than a half dozen computers that all do the same thing, but with a different interface," said an investigator based in Atlanta. "That requires more space and more training. Although multiple sponsors may use the same EDC solution, we can't get them to communicate," he stated. 

Several investigative sites commented that their offices are becoming cluttered IT jungles. "We're having a lot more trouble finding outlets to download PDA data," said a site manager, who also offered an example. "On one recent afternoon, 25 PDAs were downloading information from a Web server and another 15 were in the queue." 

"EDC definitely eliminates the hassle of storing paperwork and is a superior method of answering data queries," said a study coordinator. "On the other hand, data entry is slower and there's an occasional logjam when all seven coordinators want to input their data at the same time. Our coordinators each have six to eight studies—that would require way too many laptops," she added. 

"The necessity to add and remove users so that coordinators can enter data is often difficult," commented a site manager. "Many times, sponsors only allow a set number of users per site. Helping other coordinators with their data entry is one of the easiest ways to assist each other—but with limitations on the number of users, EDC hinders this aspect of coordinating." 

According to the CDISC survey, approximately one out of four sites report that their workload increased when e-clinical trial technologies were used. Increases in workload are largely due to sites creating paper back-up when eCRFs were used. "It's still more convenient and safer for me to transcribe information into a CRF than to use all these different databases," said a site manager. "I've just got more peace of mind knowing that I've got a hard copy." 

Only one third of investigative sites surveyed by CDISC report learning that a given trial will use eCRF and ePRO technologies during the request for proposal period. Although use of eClinical technology solutions at the site may increase workload, most sites are not compensated for this. The failure to communicate at the outset that eClinical technologies will be utilized gives the site incomplete information and sends a message that the site is not considered part of the team. As a result, study staff report ambivalence and some reluctance to get involved in e-clinical trials. 

Several sites admit that the situation is improving but still has a long way to go. "Our overall experience with help desks is a lot better this year compared to last year, but there are still a lot of bad ones out there," said a study coordinator based in Denver. "For one of our studies, we now receive notations on a Web site whenever patients call for technical support. And many companies send us quarterly updates that address technology glitches, such as a return button that doesn't respond to the first hit," she added. Several larger sites report now having an information technology specialist on staff to troubleshoot with the help desk provided by the sponsor. 

The fact that many help desks are manned from places like Singapore and India doesn't appear to be a major issue for investigative sites. "Problems are generally corrected while we're on the line," said one site manager. Another commented, "One year ago, I would never have given such a positive report for help desk support coming from overseas. It has gotten better." 

Increasing economic pressure on sponsors to conduct clinical research faster while improving safety; greater integration and access to clinical research and patient health care data; continued market consolidation; access to investment capital; and regulatory reform promoting acceptance of standards and systems compatibility are widely considered market forces that will facilitate electronic clinical trial technology adoption. Added among these forces should be the acknowledged need and the imperative for sponsors to provide greater technical support and emphasis on engaging investigative sites as partners in the adoption process.  

MS, MBA, is a Senior Research Fellow at the Tufts CSDD and Chairman of CISCRP, both in Boston, Massachusetts, email: 

Clinical Trial Insights

Lack of adequate and attentive support is preventing some sites from fully taking advantage of EDC and ePRO technologies.

The Imperative to Support Site Adoption of EDC

Food and Drug Administration officials have launched an agency-wide initiative to revise its Bioresearch Monitoring program (BiMo), which oversees inspections of clinical sites and institutional review boards (IRBs). The program ensures that applications for new drugs and medical products contain high-quality data and that human research programs protect trial participants. Planned changes fall under FDA's Critical Path initiative, which seeks to make the development of drugs and medical products more efficient and productive. BiMo modernization also reflects broader changes in the conduct of clinical trials around the world, which, in turn, are generating calls for new approaches to how IRBs do business, particularly in evaluating multisite research studies. 

For the past year, an internal FDA steering committee co-chaired by Deputy Commissioner Janet Woodcock and David Lepay, head of FDA's Good Clinical Practice program, has been discussing options for revising the agency's BiMo program. The aim is to modernize how FDA assures the integrity of research programs without inhibiting innovation. The initiative involves all FDA Centers, its chief counsel and the Office of Regulatory Affairs (ORA), which manages district inspection offices. ORA inspectors visit research sites involved in pivotal trials to check that clinical investigators follow proper informed consent and enrollment procedures, adhere to approved protocols and collect data according to an agreed-on plan. Inspectors also visit IRBs every few years to ensure that review committees are sufficiently staffed and oversee research protocols completely and correctly. 

New developments in clinical trial practices in recent years now require a new approach to bioresearch monitoring, noted Woodcock at the November meeting of FDA's Science Board. Today, researchers collect clinical trial data electronically, as opposed to the paper-based system in use when FDA established its BiMo program. Research management organizations play a more prominent role in trial operations, and more studies are being conducted overseas. Trials enroll more children and other vulnerable populations and often retain human tissues and specimens. Centralized and commercial IRBs play increasingly visible roles in monitoring the growing volume of research involving multicenter trials. And studies to test implants and complex medical devices raise new oversight issues. 

Such innovations point to the need for new standards and for rules on electronic data handling. Current FDA policies fall short in accommodating global clinical research and protecting children and other population subgroups. Woodcock recognizes a need for the agency to shift from its current decentralized research oversight program to a more uniform approach. FDA Centers now have individual BiMo offices, which vary considerably in size and resources. There is too little coordination between FDA review staff and field inspectors, who generally have limited clinical research expertise and are scattered among district offices. Lepay's small staff in the commissioner's office is responsible for setting policy for this scattered operation, but lacks sufficient resources to do so comprehensively. 

Consequently, FDA is examining how a more centralized, risk-based approach to its human subject protection program could improve oversight and address evolving legal and ethical issues. One goal is to be able to conduct more real-time inspections (i.e., while a trial is going on instead of after an application is filed). This requires better systems for targeting research sites that are involved in more critical or high-risk studies and where variation in data quality could affect the conclusions of the research analysis. FDA also seeks new technological approaches for tracking compliance by sponsors, investigators and IRBs. Several rules and guidances are in the works, which should clarify standards to ensure that clinical trials produce high-quality data. 

Many of these developments in clinical research also are generating efforts to streamline and improve how IRBs assess and approve clinical trial protocols. The Health & Human Services' Office for Human Research Protections (OHRP) is working with FDA to reduce the overwhelming volume of redundant adverse event reports now filed with IRBs. Another initiative seeks to encourage increased use of centralized IRBs, especially for multisite trials. 

The need for "alternative IRB models" was discussed at a November workshop sponsored by OHRP, the Association of American Medical Colleges (AAMC) and the American Society for Clinical Oncology. The group seeks to clarify policies for when local IRBs should cede some review responsibilities to more centralized review boards. Pharma sponsors are interested in these and other efforts to facilitate protocol review and eliminate redundancies in research oversight. 

OHRP officials emphasized that current regulations do not require a local IRB to approve all research proposals involving local investigators. FDA issued guidance last March that encourages local IRBs to share oversight responsibilities for multisite studies with central boards. The guidance notes that a reviewing IRB should reflect community values, but offers suggestions for addressing these needs without duplicative oversight (guidance available at 

www.fda.gov/OHRMS/dockets/98fr/05d-0103-gdl0001.pdf

The workshop provided a forum for representatives of academic research institutes, IRBs, government, and industry to address the range of issues that make local IRBs reluctant to cede oversight responsibilities to other review organizations. A survey of medical schools indicates that local IRBs fear using central review boards due to concerns about liability, added costs, loss of local representation and lower quality service, explained AAMC Senior Vice President David Korn. However, cancer researchers noted that many local review boards lack the expertise needed to evaluate complex protocols that involve multiple sites. 

Participants urged OHRP and FDA to issue more explicit guidance to encourage local institutions to adopt new review models. The group also discussed ways to strengthen operations at all IRBs, encouraging the use of model informed consent forms and common data submission standards. These measures can help small IRBs deal with larger studies, as can Web sites such as 

 that post review decisions and information contacts. More cooperative review approaches can benefit from "crisp" agreements between local and central IRBs that spell out criteria for using alternative review models and address liability concerns, noted Lynn Cates of the Veterans Administration. 

There was some agreement that certain types of research might be more suited for centralized review, such as low-risk Phase III and Phase IV trials involving multiple sites, as compared to investigator-initiated studies of innovative treatments. Increased oversight of IRBs by FDA and OHRP to identify well-run and compliant review boards also may raise the comfort level at local IRBs asked to cede responsibilities to a central board. 

A conference report describing these issues is slated for review by the Secretary's Advisory Committee on Human Research Protections. A larger public meeting on best practices at central and local IRBs will shape recommendations for how OHRP and FDA could clarify policies to encourage the use of new IRB models. Local IRBs are an "essential" component of the nation's human subject protection system, noted OHRP director Bernard Schwetz, who cautioned that efforts to adopt alternative oversight approaches should be careful not to erode the strengths of the current system.  

View from Washington

Changes prompt new oversight approaches by FDA and research institutions.

Clinical Inspections, IRBs Face Overhaul

In the early 1980s, Europe was seen by the United States as a mosaic of peoples, cultures, and medical practices. Contrary to the American multicenter clinical trial, the Europeans did not have enough in common to allow clinical data to be shared and collated. The clinical climate in the United States was convinced that the European data would be influenced by the genetic differences among ethnic groups, national differences in the diagnosis of disease, variations in the use of medicinal products for treatment, and differences between health care systems. 

 Jean-Pierre Tassignon, MD, PhD, FFPM, MBCPM 			

At the present time, the cross-border Good Clinical Practice (GCP) movement is a reality, and it is driven by sponsors and CROs in need of patients for critically important clinical trials as well as investigators and countries willing to invest in all the drivers of GCP. The drivers include new legislation, GCP inspectorates, ethics committees, curricula in pharmaceutical medicine, conferences, etc. The movement started from regions with advanced GCP legislation and recruited countries with enough resources to meet the same clinical standards. 

The movement has been very successful, but it has a price, as we learned in the European Union (EU) following the implementation of the European Union Clinical Trial Directive (EUCTD). Eastern Europe (per capita GDP is 6000–13,000 Euro/year) is capable of paying the price, as the region is undergoing rapid economic growth and its Gross Domestic Product (GDP) per capita is catching up with the West. 

Not everyone, however, is capable of paying the price in the EU. In May 2005, one year after its implementation, the European Forum for Good Clinical Practice (EFGCP) held a conference in Brussels on the EUCTD. The conference attendees reported that: a) there was a dwindling number of academic research studies across the Union; b) a proportion of Phase I studies with new medicinal products were exported from the EU to North America; c) statistics about Phase II and III industry-sponsored studies were still inconclusive with regard to judging the impact of the EUCTD; and d) the cost of complying with the EUCTD was expected to impact the hardest on industry-sponsored studies in Phase IV. In this climate, the academic world in Europe was not prepared to comply with the directive's mandates, whereas the pharmaceutical industry was working hard to comply with Phase II and III mandates. At this time and due to the strengthening of the Euro and capacity issues, the Phase I trials could be done in North America. The diminishing return of marketing trials on prescription in Phase IV is probably insufficient to justify a sudden increase in regulatory compliance costs. 

The EU rapidly tackled the issue of academic studies by issuing the GCP Directive, which allows member states to accommodate the EUCTD to the specific environment of academic research. However, at this time, it is the speed of implementation of waivers by the member states in their national legislation that remains a challenge. 

Dozens of European startup biotech companies that were ready to begin first clinical trials had to postpone their projects, beef up the IMPD, and collect more funds in order to finance additional expertise for clinical trials costs. 

The EFGCP conference concluded, with cautious optimism, that the industry-sponsored compartment in European clinical research would regain pre-EUCTD levels of intensity after an adjustment period, and that the academic compartment would do the same after implementation of the new accommodations, if any. 

However, given the standards set by the EUCTD, GCP and per capita GDP, which appears to go hand-in-hand, the question still remains open as to whether countries with a per capita GDP below 5000 Euro/year have a chance of joining the drug development movement, with the exception of some specific diseases such as tropical diseases. 

At the same time Russia, China, and India have invested in the drug development movement. Russia is witnessing a strong inflow of petrodollars, part of which is being reinvested in the health care system. In May 2005, the EFGCP hosted a delegation from the Chinese State Food and Drug Administration and the Shanghai Municipal Food and Drug Administration. The purpose was to exchange views on systems for ethics review in Europe and in China. This country, with 1.3 billion inhabitants, is readying itself for clinical trials on a grand scale. India is on the same path. Both countries are at the beginning of a Himalayan task, given their GDP per capita per year. 

The WHO is further contributing to extend the borders of the GCP world via programs destined to enhance the ethics review capacity in less-developed countries and train investigators in GCP.  

The EUCTD is creating a stimulus for the globalization of clinical trials, as the more advanced FDA regulations created a stimulus to export trials from the United States to Europe 20 years ago (trials were somewhat less expensive than in the United States then and quality of clinical research in Europe was improving quickly). GDP per capita in Western Europe was approximately half that in America. Today, Eastern Europe has a per capita GDP approximately half that in the old EU. Eastern Europe is adopting the EUCTD quickly and is increasing its clinical research output. Emergent countries like India and China are at the beginning of developing a clinical research capacity to world standards. A doubling of their GDP per capita within the next decade should bring them to the level of clinical research productivity now observed in Eastern Europe. 

MD, PhD, FFPM, MBCPM, is chairman, board of directors, European Forum for Good Clinical Practice, Brussels, Belgium; lecturer, Pharmed, Université Libre de Bruxelles, Brussels; and executive vice-president, PSI Pharma Support International AG, Zug, Switzerland.

Guest Commentary

As some EU countries struggle with the Directive's regulatory demands, emerging markets such as China, India, and Russia continue to bolster their clinical research and drug development programs.

The Globalization of Clinical Trials

From a historical perspective and subsequent to the political changes in Central and Eastern Europe, the G-7 summit held in Paris in mid-July 1989 established a special instrument of financial support for Poland and Hungary to Assist Restructuring their Economies

  (PHARE) and later extended it to cover other European countries in transition. The PHARE program was one of the three pre-accession instruments financed by the European Union (EU) to assist the applicant countries of Central and Eastern Europe in their preparations for joining the EU.  

In view of the EU enlargement in 2004, which was going to increase the number of member states from 15 to 25, there was a need to prepare the candidate countries so that legislation and practices related to medicinal products would be equivalent in all member states and in the European Economic Area (EEA) countries Norway, Iceland, and Liechtenstein, since these three countries follow the EU regulatory framework for medicinal products.  

For that purpose, the Pan-European Regulatory Forum

  (PERF) was created. It went through several stages of development between 1999 and 2004, designated as PERF I, PERF II, and PERF III. By the end of PERF I, the authorities considered the Good Regulatory Practices (GRP) a quality system and the following description of GRP developed during PERF II: A quality system to ensure that the users of medicinal products, the applicants, the regulators are satisfied with the scientific advice, opinions, the establishment of Maximum Residue Levels, inspection and assessment reports and related documents, taking into consideration legal requirements and guidance in order to protect and promote human and animal health. 

The timely delivery of the services, the opinions provided by a regulatory authorities' network, and its quality and consistency can only be ensured if quality and regulatory compliance is built into every step of the process, and the process capability is enhanced by continual improvement. A network of regulatory authorities is not different from a regionally or globally acting enterprise with subsidiaries in different countries, with the need for quality and consistency to ensure safety, efficacy, and quality of their medicinal products. A network organization requires a smooth operation, which only can be achieved by implementing an integrated quality management system.  

Benchmarking the management systems of the European competent authorities was proposed to assure the quality of the authorization and supervision of medicines for human and veterinary use. Individual integrated (quality and risk) management systems were compared using the ISO 9004:2000

  (self)-assessment questionnaire, with the purpose of enriching, learning, and teaching to find best practices that are (cost)-effective, efficient, and feasible. Benchmarking is about exchanging experience, about "ad hoc" consultancy by colleagues working in a similar environment for different organizations but with a similar task, and it ensures continual improvement of the EU/EEA Medicines Agencies' Network.  

The use of an International Standard and Guidance for benchmarking allows mutual understanding between partners, not only in the EU/EEA, but worldwide. Moreover, a questionnaire based on the ISO standard and guidance facilitates the implementation of an ISO 9001:20001 quality management system by management with the endeavor to achieve ISO 9001:2000 certification of their Agency.  

During a benchmarking visit and assessment, which is different from an inspection or audit, there is a continuous enriching interaction between the visiting colleagues from other agencies and visited staff and management. The assessment is fully transparent, and the visiting team discusses and decides on the rating for an assessed process/system in the presence of management and staff. It is this process of exchange that makes benchmarking such a good, value-adding tool. 

In the PERF framework, benchmarking visits to 17 Agencies/Ministries took place. The visiting teams consisted of EU National Competent Authorities, European Medicines Agency (EMEA) or European Directorate for the Quality of Medicines (EDQM) staff (auditors, inspectors or quality managers), and similar staff from, at that time, the EU candidate countries. The anonymous database, resulting from the PERF benchmarking assessments by the visiting teams, is available for National Competent Authorities (NCAs) at the EMEA, and is full of valuable information reinforcing the rating system thanks to the description of evidence substantiating the assigned rating.  

Since the PERF benchmarking self-assessment and anonymous exchange of results was a useful tool for management of the EU/EEA Agencies' network, the European Commission assigned to the NCAs the task of developing the EU benchmarking system further with the EMEA for medicines for human use and veterinary use "to contribute to the development of a world class regulatory system for medicinal products based on a network of agencies operating to best practice standards."			

 PhD (Chem), PhD (Biochem), FIQA, is integrated quality management advisor, Directorate, European Medicines Agency, 7 Westferry Circus, Canary Wharf, London E14 4HB, UK, +44 (0) 20 7418 8556; fax +44 (0) 20 7418 8409, email: 

europa.eu.int/comm/enlargement/pas/phare/

2. PERF III: The third Pan-European Regulatory Forum on Pharmaceuticals run from January to December 2003. The candidate countries involved in the PERF programme were Bulgaria, Cyprus, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Malta, Poland, Romania, Slovakia, and Slovenia. The purpose of PERF III was to help candidate countries prepare their regulatory systems before accession to the EU. The benchmarking visits were funded by the European Commission PHARE programme for 10 Central and Eastern European candidate countries. Cyprus and Malta participated without PHARE support 

3. ISO9004:2000 Quality Management Systems—Guidelines for Performance Improvements. 

4. M. Korteweg, "Benchmarking of Good Regulatory Practice—Quality Management Systems in the Framework of PERF," 

5. M. Korteweg, "The Challenge to Ensure Good Regulatory Practices in a Growing Network of Authorities," 

6. ISO9001:2000 Quality Management Systems—Requirements. 

GRPs are not another set of guidelines or "additional hurdles" prepared by authorities.

Good Regulatory Practices: Another Set of "Things to Do"?

Timing is everything in effective medical care—and the European Medicines Agency certainly got close to capturing the moment with its latest draft clinical guidance. As the world's population, trembling at the prospect of imminent extinction in an avian flu pandemic, developed a sudden and passionate interest in prophylaxis, the agency released a concept paper that appeared to respond to popular concerns, with a focus on vaccines. 

Closer inspection revealed that the agency was not providing an instant solution to potential obliteration of the human race. More prosaically, it was offering a concept paper for a guideline on the conduct of pharmacovigilance for vaccines. Not quite so sexy. But although the world may have shrugged its shoulders dismissively and shifted its frantic search for salvation elsewhere, the document is worth a glance for those with a more mature grasp of what is at stake in the clinical aspects of medical care. 

The paper proposes the development of a guideline on the conduct of pharmacovigilance for vaccines used by all age groups for prophylaxis against infectious diseases. It covers the steps in the pharmacovigilance process, types of vaccines, different target populations, and different stakeholders, with particular emphasis on small children, a major population group that routinely receives vaccines. 

The starting point is that prophylactic vaccines are different from most other medicines in that they are generally administered to wide and healthy populations, so naturally a very high standard of safety is to be expected. Consequently, pharmacovigilance merits particular attention, not least in respect of assessing whether any aspects of the system need to be enhanced to ensure adequate protection of public health. 

As the concept paper notes (irrespective of the current popular panic over avian flu), vaccine safety issues have been discussed increasingly in the public arena. In an implicit reference to heavy media coverage of suggestions that infants have suffered serious side effects from some routine vaccinations, it comments coyly on "some safety signals" that have raised serious public concerns, reducing trust and acceptance of vaccines—with an impact on the effectiveness of vaccination programs. 

So the guideline will focus on methods and tools to investigate the tolerability and safety of vaccines. Since any safety concern over a vaccine concerns a high number of subjects, safety concerns need to be quickly evaluated. And although vaccination programs differ between member states, the same vaccines are authorized and sold across the EU, so a problem arising with a vaccine in one member state might have impact on the safety of the same or similar vaccines in all other countries. 

In addition, as immunization now becomes universal, surveillance should also be universal, the concept paper argues. For new vaccines now in development or clinical testing—such as antimalaria, anti-HIV, or for prophylaxis of cervical cancer, and which are expected to deliver large benefits for public health—benefit–risk evaluations have to consider safety and efficacy aspects for the individual vaccines and for public health. So the guideline will underline that validated, robust and widely accepted methods are needed for vaccine safety surveillance. 

Given the limited immediate individual health benefit from most vaccines, adverse reactions are understandably considered less acceptable, especially if the incidence of the infectious disease in the target population is low or is reduced as a result of a successful vaccination campaign. 

This narrow therapeutic margin makes it necessary, suggests the agency's paper, to conduct intensive investigation of even rare suspected adverse reactions. There is a need for clear case definitions of adverse reactions following use of vaccines for proper case ascertainment and assessment, and for long-term follow-up for delayed adverse reactions in a postmarketing setting. Similarly, a new approach may be needed to deal with nonserious adverse reactions if these impact on the acceptability of a vaccine and translate into a low coverage rate. 

Other areas identified as requiring closer study include the age-relatedness of adverse reactions, methods to assess causal association of serious and rare adverse reactions, special risks for infection of others associated with the administration of live attenuated vaccines, batch-relatedness of adverse reactions—in light of variations in the manufacturing process between batches—and proper postmarketing investigation and assessment of changes in the manufacturing process which, even if small, may have implications on the safety profile of a vaccine. 

The concept paper envisages taking account of the role of a wide range of stakeholders, ranging from competent authorities to those who receive vaccination (and in the case of children, their parents), to health authorities responsible for vaccination programs and batch release and authorities evaluating epidemiology of vaccine-preventable infectious diseases. Equally, the respective roles will be considered of healthcare professionals, manufacturers, the World Health Organization, and the media. 

It will address safety aspects in different target groups, such as infants with a developing immune system, immuno-compromised patients, and elderly patients. And it will assess the safety considerations of different types of vaccines—including vaccines based on new concepts and new technologies or delivery systems—as well as the special safety aspects of stabilizers, preservatives, adjuvants, and other residual material in the final product. 

Although this is only a draft suggestion at this stage, the agency clearly has some firm ideas on what the final shape of its guideline will look like. Already EU rules for medicines authorization regard pharmacovigilance planning as an essential element of an application, with risk management plans as a standard procedure where merited. But the concept paper also envisages special postauthorization pharmacovigilance considerations, linked to the different characteristics of each vaccine, whether it is new or well-established. 

It suggests manufacturers and authorities should develop predefined check lists or formats for postauthorization reports of adverse reactions that can be anticipated from experience with comparable vaccines. "This is essential to ascertain relevant clinical information in a consistent way in order to ensure the high quality of the causality assessment of an individual case," the concept paper urges. 

Similarly, the appropriate case ascertainment is crucial for a valid spontaneous reporting system. Adequate follow-up of serious spontaneous adverse reaction reports should be guaranteed, and the importance of causality assessment on established criteria will be stressed. Adverse events following immunization should be considered under the headings of "vaccine-induced," due to the intrinsic characteristics of the vaccine preparation and the individual response, and "vaccine-precipitated," triggered by administration of a vaccine but which may also have occurred later or in other circumstances. 

Postmarketing safety studies should investigate adverse reactions or risks that are not identified or fully characterized prior to authorization, such as rare but serious adverse reactions, reactions with delayed onset, and reactions in subpopulations. 

And the overall impact of postauthorization surveillance should provide reliable estimates of the incidence of adverse reactions in the target population, the causal relationship between vaccine and adverse event, and risk factors predisposing to specific adverse events. The guideline would present specific advice and considerations for when and how specific studies should be conducted. 

Meanwhile—and unsurprisingly—the European vaccine industry has been maximizing the opportunity that avian flu has provided, and showcasing its merits and its key messages. The European Vaccine Manufacturers (EVM) issued a statement in late 2005 on human influenza pandemic vaccines outlining their view of the current situation and the future prospects. 

In the event of a pandemic, vaccines will be the best specific way to control the disease, and will be needed as soon as possible and in very large quantities, it pointed out boldly. And, it claimed, somewhat stridently, it has been "actively involved in addressing this public health challenge"—notably with an action plan it proposed in February 2004, which urged a long-term commitment between the industry and the European and national authorities to make sure answers were available before the threat becomes a problem. 

Some positive progress has been achieved, the statement records. The European Medicines Agency has instituted an accelerated procedure for the development of prototype pandemic influenza vaccines. Manufacturers are engaged in the development of prototype pandemic vaccines, upgrading facilities to produce clinical batches, and conducting trials of specific monovalent formulations that could be available within a year. And talks are underway on the creation of a public–private partnership to push development and to promote increased interpandemic influenza vaccination uptake. 

But significant challenges still need to be overcome, says the EVM. 

In particular, the current 20% level of vaccination of the European population "is not adequate to secure sufficient quantities of vaccines in a pandemic situation," and additional investments are needed to increase coverage rates and production capacity. 

Europe remains far behind the policies developed by the United States, Canada, Australia, and Japan to support the development of pandemic vaccines through contractual arrangements with manufacturers for vaccine formulations and increased manufacturing capacity. Financial support from public health authorities is needed to boost industry research and development both in the short and long term. And not enough EU member states have reached the national advance purchase agreements with manufacturers that are necessary preconditions to the lengthy process of increasing production capacity. Nor has adequate provision been made by the authorities on major questions ranging from supplies of raw materials to liability or to allocation of stocks in the event of an emergency.  

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

View from Brussels

New paper from the European Medicines Agency explores future vaccine guideline.

Two-Timing on Today's Vaccines?

Much has been said and written during the past year or two about the urgent need to conduct more pediatric clinical trials, but a less fashionable topic is the importance of including older people in clinical research. 

 331, 1036–1037), an eminent Scottish geriatrician presented a compelling case for involving the elderly in more trials. Prof. Marion E.T. McMurdo, head of ageing and health at Ninewells Hospital and Medical School in Dundee, UK, argued that the benefits shown in trials in younger people may not apply to older people. 

In the following question-and-answer article, she elaborates on this subject. 

Q. Why are the elderly in need of clinical trials specifically geared to this age group?

 Older people comprise almost one in five of the population of most developed countries, yet are systematically excluded from participation in clinical trials. To be able to provide the most effective treatment and management for our growing older population, we must have good quality trial evidence to underpin this. The lazy option of simply extrapolating results from younger populations may be very misleading. 

Q. What special problems exist when conducting clinical trials in the elderly?

There may be particular issues relating to communication—deafness, visual, and cognitive impairment are relatively common in older age groups. Older people will often have a range of comorbidities (and concomitant medication), which may make trial results less "clean." Practical issues about transport, mobility, and access should also be considered. 

Q. Does the informed consent process need to be changed for the elderly population? If so, what do you suggest?

older people need any special process for informed consent. Researchers should, however, be sensitive to the fact that older people may wish time to discuss possible trial participation

with family and friends. However, it is encouraging to note that older people report a high rate of willingness to consider trial participation when approached. 

 editorial that protocols need to be specifically designed for the elderly, or modified exclusion criteria should be used to allow inclusion of patients with comorbid disease and multiple medication. Has this been done elsewhere, and has it been shown to work successfully?

 Many of the major clinical trials worldwide have recruited middle-aged men with a single pathology, and no concomitant medications. But in the real world, typical heart failure patients for example are over 75 years of age, female, with numerous comorbidities and are in receipt of multiple medicines. It must be possible to ensure that more protocols are designed in a way that permits the inclusion of the population most likely to be prescribed the drug once licensed. 

Q. Which adverse reactions tend to occur most frequently in elderly subjects, and how should they be handled?

The type of adverse events will depend to a large extent on the type of compound under evaluation. However, it is known that prescription of psychotropic drugs, for example, is associated with an almost doubling in the risk of falling in older people. I would welcome the development of trial protocols evaluating such compounds that specifically seek to systematically record falls rates. 

Q. What practical actions can investigators, sponsors and contract research organizations take in order to overcome the special problems of the elderly population?

I prefer not to think of the elderly population as having "special problems." They are just people who have had rather a lot of birthdays. Unfortunately, this deters investigators from including them in clinical trials. Rejection proposals intending to set arbitrary and unjustified age restrictions as unethical would be an excellent starting point. 

Q. Overall, what suggestions or recommendations can you offer the global pharmaceutical industry regarding inclusion of the older population in clinical research?

Cardiovascular disease, cancer, and diabetes are diseases that affect large numbers of older people, yet the depressing fact is that at present the older population is being deliberately excluded from participation in the major clinical trials in these key areas. The pharmaceutical industry should devise trial protocols targeting trial populations who are most likely to be prescribed the medication once licensed. This will confer the advantage that the trial results will be more generalizable. Conferring with specialists in old age medicine about trial design might make this process considerably easier. We need to start getting this right for today's older people, and don't forget that very soon we too will be joining the ranks of the older population.  

Prof. Marion E.T. McMurdo elaborates on the importance of including older subjects in clinical trials.

Applied Clinical Trials-01-01-2006