Is 90% of all data collected rubbish? A provocative keynote debate at the recent DIA 2nd European Clinical Forum explored this question.  

Specific to electronically delivered data, Nick Lucas of INC Research, UK, said it is never clear whether what is received is in fact what was requested. Statistics show that 100% of all queries are generated by 40% of all validation checks, raising the question as to what the rest of the validation checks are checking—probably unnecessary data.

Other statistics show that less than 5% of the data in a database changes after it has been entered. Therefore, more than 95% of the data never changes post entry. This means data cleaning efforts are focused on a very small amount of the data, and it could be argued on the need to focus on the 95% of untouched data. Certainly it may be clean, but it may also not be the focus of the Safety/Efficacy parameters required of the study and, therefore, superfluous.

The sheer volume of queries—1 in 10 CRF pages, 10 in 10 CRF pages, or 20 in 10 CRF pages—is an indicator of poor quality data. Using EDC means that the data quality at point of entry should be better. But sites complain that the computer keeps raising queries as data  is entered. The answer is to persuade sites to enter better data and the system will not keep raising queries.

Jane Barrett of the Barrett Consultancy, noted that in research, "We do not know, what we do not know." It may well be that 90% of data will show nothing, either positive or negative, but knowing that nothing changes is also useful information. Thalidomide was tested in development in one species, and no teratogenicity was seen. When later tested in another species the teratogenicity seen in humans was confirmed. If the testing is not down in that second species, we do not know all the answers. It is indeed possible that only 10% of data is useful, but the other 90% normal is needed to show that.

Joris Cauquil, of AMITIS/Effi-Stat, France, questioned whether the answers to queries are real, or merely represent the investigator trying to pacify the sponsor. Also, is it necessary to gather so much data, bearing in mind that the more statistical tests performed, the more likely a false positive will result. It is far more important to ensure accuracy of measurement and reliability, both of clinical measurements and software, and to ensure that the criteria of the study are met. 

Linda Talley of Eli Lilly, in the United States, reminded the audience that clinical data is the foundation of drug development, and the data collected are used by a variety of different individuals for different purposes. The trial data collection strategies for Phases I, II, III, and IV are very distinct and serve different purposes. But Talley emphasized a need to look at the whole drug development program and not just individual trials when collecting data and determining data needs. The stance should always be addressing data quantity collected versus quality. 

, MBBS, FFPM, LLM, is the Treasurer of the British Association of Pharmaceutical Physicians, and is principal of The Barrett Consultancy, 

Articles

Global News

Jane Barrett discusses data quality as she addresses the question raised by DIA's 2nd European Clinical Forum: Is 90% of data rubbish?

What's Behind Clinical Trial Data?

The mountain heaved and brought forth a mouse. After almost a year of investigation, the EU's antitrust authorities delivered their preliminary report in late 2008 on their investigation into the pharmaceutical industry's supposed sabotage of competition through collaboration, collusion, and conspiracy. Even with 426 pages of the report behind them, officials responsible still do not feel in a position to level any specific accusations, still less to name names or press charges. 

The interim report on the investigation by the EU's commissioner for competition, Neelie Kroes, concluded that "competition in this industry does not work as well as it should." But she has adduced little evidence to support that any failings are the consequence of improper activity.

The hollowness of the case was instantly underlined by the European Federation of Pharmaceutical Industries and Associations (EFPIA). It said it was "disappointed" that officials had tried to "mischaracterize the industry as anticompetitive," particularly by the use of "selective quotations" from material seized from companies in the course of dawn raids.

"Those quotes simply show how innovators have rightly sought to protect their inventions and illustrate the highly competitive nature of innovation in this sector...They are not evidence of competition law infringements, as the report itself recognizes," retorted EFPIA. 

The industry analysis of the report is uncharacteristically harsh for a sector that has always preferred the velvet glove to the mailed fist for its European diplomacy. "The report acknowledges that patents are key to pharmaceutical innovation and should be protected. It then contradicts itself by questioning the right of the industry to use perfectly lawful practices—such as patent portfolios, patent litigation, and the release of improved medicines," says EFPIA. "Furthermore, the report does not establish that such activities deter generic entry because the facts on generic entry tell a different story."

Those who wish to make their own assessment of how far the EU document validates its claims of subverted competition can do so at 

http://ec.europa.eu/comm/competition/sectors/pharmaceuticals/inquiry/index.html

 readers, it is perhaps more valuable to trawl through the magma of this voluminous report for information of more specific interest to the clinical trials community. 

The report's presentation of the current state of the sector in Europe offers some insight into how officialdom views the industry and its attempts to create new products. It says the sector is "vital to the health of Europe's citizens" because "Europe's patients need access to safe, innovative, and affordable medicines." 

It values the EU market for prescription and nonprescription medicines at €138 billion ($200 billion) ex factory and €214 billion at retail prices—retail expenditure of approximately €430 for each EU citizen in 2007. The market for prescription medicines was worth around €120 billion at ex factory prices, it estimates. 

The inquiry covers 2000–2007, and focused on 43 originator companies and 27 generic companies that "cooperated actively," representing, together, over 80% of the Rx market. 

Findings include calculations that originator companies spent on average 17% of their turnover from Rx meds on R&D worldwide in 2000–2007, with 1.5% of turnover spent on basic research, and the rest mostly on preclinical and clinical trials and tests. "According to the submissions received by the respondent companies," preclinical and clinical trials "are generally financed by the companies' own resources...and financial support received from governments or other sources is not significant." And "the development phase, in particular Phase III trials, is the most expensive." 

For large firms, "research is an international activity in the sense that it can be located wherever a suitable research environment exists. Once a potential compound has been identified, there seem to be some synergies for the development phase (preclinical and clinical trials), although certain trials need to be carried out nationally or regionally." 

An average of five years is reported for "a potential medicine to go through the three clinical trial phases," as the report expresses it, with a range of two to 10 years. For the 20 best-selling molecules, it calculates the period between first patent application and market launch at between six and 10 years, and for a wider sample of 141 products for which complete data was available, the average was 8.6 years. 

Somewhat skeptically, the report observes: "The originator industry claims that the cost of a new medicine from basic research to launch amounts to between US $800 million and US $1 billion (this figure includes the costs of failed projects)," adding "Some respondents have suggested, however, the costs are closer to $450 million."

Expenditure on marketing and promotional activities is estimated at 23% of turnover—"thus about one third more than they spent on R&D as a whole," the report adds with an unmistakably censorious air. Similarly, the report cites industry figures indicating that as few as one in 5000–10,000 compounds tested are successfully launched, before going on to remark: "In the course of the sector inquiry it was not possible to verify this data, as many companies claimed that they were unable to provide the requested information."

In a changing environment—in terms of competition, health care technology, and economics—originator companies are, according to the report, "reengineering their business strategies" to concentrate particularly on patient-focused personalized medicines and on biopharmaceuticals. It states that two-thirds of the companies consulted said they are involved in, or intend to extend their activities to, biopharmaceutical-based medicines in the immediate future in expectation of growth faster than the traditional market. 

Companies also indicated that the success rates for biopharmaceutical-based medicines are twice as high as those of chemical molecules in preclinical and clinical development, and have fewer side-effects, greater potency, and better selectivity for specific diseases and patient groups, the report notes. 

The investigation observed that originator companies rely heavily on innovations from third parties: More than one third of all new medicines in the marketing approval phase were acquired from outside the company, it found. Large pharmaceutical companies are increasingly in-licensing new products, the report adds: "Currently 25% of the molecules in clinical development have been acquired from other companies"—including smaller firms, which it concludes "shows the importance of smaller firms for maintaining the innovative character of the pharmaceutical sector." 

The report is not entirely dismissive of industry's concerns over the difficulties of developing and launching effective new medicines. "Discrepancies between different regulatory agencies as regards to the assessment criteria are of concern for companies," it notes, without any perceptible incredulity. 

"Despite the European regulatory framework, companies reported the increasing volume of data requested during the evaluation procedure and the need for duplicative assessments for certain national agencies. A number of companies suggested that more coordination should be developed among agencies...some originator companies specifically expressed a need for Europe-wide consolidation of the requirements in the design of clinical trials." 

It faithfully cites verbatim some of the observations it has gathered on these difficulties during the course of the inquiry. Examples include: "The conduct of multicenter, multinational clinical trials in Europe remains difficult and [the company] would welcome the earliest possible introduction of an optional centralized procedure for European multinational clinical trials," and "Implementation of the Clinical Trials Directive requirements is cumbersome, creates a great drain on resources, and is not consistent across member states...so the benefit of a single approach has been partially negated." 

Equally, it cites companies' concerns over the lack of international harmonization, including "increasing differences between scientific advice from the USA and Europe," and different requirements expected for the clinical trials of the same product between Europe and the United States. 

The debate over these preliminary findings is just beginning. This spring the EU authorities will publish a final report. Some of the debate may prove helpful in exposing and even remedying difficulties in developing medicines, some may prove less helpful, complicating the process of protecting innovations. In this respect, Kroes has made clear that she is still on the antitrust warpath.

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

View from Brussels

What antitrust authorities have uncovered so far in their search for sabotage.

Of Mice, Mountains, and Magma

Features include study monitoring and query management tools

 (Cambridge, MA) announced the availability of OpenClinica 2.5, its open source clinical trials software for the clinical trials industry.

The new release features new study monitoring and query management tools and reports; import of data from external sources; enhanced eCRF features, including scoring, multivariate edit checks, and rules; user roles for monitors and data managers; electronic signature capabilities; improved auditing and logging capabilities; and simpler CRF upload.

The new version has also been translated into three additional languages: French, Italian, and Portuguese. It also features support for the Oracle database. It's available for free download at 

Includes tracking for metrics on investigative site performance

 offers the next release of its eClinical Product suite for global clinical trials. Detailed clinical trial information can be found in this new version. For example, with this version of DATATRAK eClinical, as long as this platform is consistently used, clinical trial sponsors will be able to characterize the historic quality of a research site before the clinical trial is started, based on investigative site performance.  

In addition, the Query Manager now filters on Data Point Changes to see if team members have responded to queries. Standard reporting additions have been made to the study homepage to include time averages for various study activities, form counts, breakdown of data point status, and more. It also includes Japanese/Kanji-character translation.

CDISC standard applied to forms for EDC/CDM product

has included preconfigured and validated electronic case report forms (eCRFs) that comply with the CDASH Version 1.0 standard for collection of clinical safety data. These eCRFs are mapped to SDTM-compliant reports.

Used in conjunction with Medidata's Rave EDC and CDM product's study design and reporting capabilities, will enable sponsors to jumpstart EDC set-up, tailor studies to specific needs more quickly and efficiently, and reduce the risk and complexity involved in adopting a standards-based approach to study build and submissions.

eShowcase

The latest eClinical software in the clinical trials industry.

eClinical Software: January 2009

 (Boston, MA) as director of regulatory affairs and associate medical director, 

 will become responsible for managing all quality assurance and regulatory affairs operations.  

Upon taking on the role as director of research services at 

 will have the responsibility of performing all scientific research writing activities, providing full life cycle support from clinical study protocols through regulatory submission as well as post approval activities.  

Previously serving as the director of the Office of Human Subjects Research and a bioethicist at the NIH, 

, MD, JD, has been appointed as the director of the 

 (Raleigh, NC) pediatric team in the development of program strategies and consideration for clinical trials in neonates, children, and adolescents is 

, the new principle pediatric strategist.  

, MD, as the company's first chief development officer, allotting him the responsibility of coordinating the group's expanding therapeutic antibody development activities.

With more than 18 years of experience in heading financial and operational management efforts in other organizations, 

The Association of Clinical Research Professional's

 (ACRP; Alexandria, VA) acting president and chief executive officer.

 will become the new vice president of operations for 

 (Mumbai, India) headquarters located in Mumbai, India.

After recently serving as chief executive officer for 

 (Gif sur Yvette, France) vice president of U.S. operations.

As the new director of business development for 

 will lead the business development team and work toward improving client relations.

 to the position of director, toxicology and pharmacology, where he will be responsible for all work conducted by the company's study directors, as well as the peer review process and delivery of toxicological reports.

 (Basking Ridge, NJ) new senior vice president of business operations position, as well as chief business officer, in which she will bring with her almost 20 years of biopharmaceutical industry experience. 

, vice president of North American sales, and 

, vice president of EMEA and APAC sales, to its sales team. 

(Amersham, UK) as the new head of global resourcing, 

, also vice-chair of ICR's Resourcing Special Interest Group, brings with him over 25 years of experience, which includes working in sales, sales management, marketing, and as a senior resourcing consultant. 

 (New York, NY) ASPire to Win partnership program and will be implementing Medidate Rave into its existing services.

 (Basel, Switzerland) was able to provide TQT data, which was acquired, analyzed, and formatted by 

(Bethesda, MD) for submission into the Telemetric and Holter ECG Warehouse's (THEW) international repository.

(Boston, MA) to provide a complete imaging service for clinical trials.

In an attempt to improve GCP in China and after entering into an alliance with the 

 (SCRC; Shanghai, China) will promote the U.S.-based organization's training programs nation-wide in China. 

With a new business unit that focuses on clinical trial data management and plans to further expand into the clinical trial market, 

 (Redwood Shores, CA) Clinical applications to support its initiatives.

(Tokyo, Japan) has begun its first self-designed project using 

 (Cleveland, OH) eClinical platform in a Japanese clinical trial.

Among 320 companies, evaluated by 44 global technology experts, 

 (Waltham, MA) emerged as The World Economic Forums' selection for Technology Pioneer of 2009.

, MD, cofounder, president, and chief executive officer of 

 (East Norriton, PA), a biotechnology company, has been awarded the Ernst & Young national Entrepreneur of the Year within the emerging company category.

In recognition of its research of genetic techniques in cancer treatment, 

 (Cambridge, UK) has been awarded the "Best Business Proposition Award" at the UK-based Medical Futures Innovation Awards.

After completing the necessary requirements, 

 (Greenville, NC) has been named an ASQ-Certified Manager of Quality/Organizational Excellence, which is administered by the 

 (Mountain View, CA) was awarded "Best Overall Company of the Year," for service businesses with up to 100 employees, at the 5th annual Stevie Awards for Women in Business.

The U.S. Department of Defense (DoD) has contracted with 

 (Waltham, MA), requiring its support in the FDA's sponsored drug safety initiative, which sets out to access DoD health care data for a more rapid assessment of drug safety issues.

 (Durham, NC) has completed its voluntary inspection that covered the group's main sites including, Craigavon, UK, Audubon, PA, and Durham, NC. All inspections returned with no major failure notices. 

 (Indianapolis, IN) is the only commercial clinic to host Phase I trials in Indianapolis. 

 (Dublin, Ireland) medical imaging division has launched a cardiac echocardiography (ECHO) analysis software solution, which now allows ECHO images to be utilized in clinical trials.

Marking its 30th anniversary of the Annual Spring Conference and Exhibition, 

 (Bourne End, UK) has updated the events' format to include featured speakers across the specified topics of therapeutics, raising standards, shaping knowledge, and developing professionals.

 (Strasbourg, France), formerly Faust Pharmaceuticals, will allow companies access to its G Protein-Coupled Receptors (GPCRs) technology and will also be conducting early development of its products.

In response to the dropout of two U.S. competitors from the European market as well as the closing of a German lab facility, 

 (Munich, Germany) has increased its European project and data management team by 30% in preparation of an expected rise in business.

To ensure timely and secure data communication, 

 (Milton Keynes, UK) has chosen to utilize IT Farm's Web-based IT, which allows the company, including its offices in Russia, India, and China, to access all of its programs, files, and share data through a secure Web site.

Adding to the research and development core that is Research Triangle Park, in North Carolina, 

(Research Triangle Park, NC) is opening its new U.S. headquarters and analytical lab facilities in the area.

(Dallas, TX) has expanded its services by adding a Phase I unit to its already existent Phase II-IV facility.

Marking its fifth location in Latin America, 

 (Boston, MA) has opened an office in Lima, Peru, where it will provide regulatory consulting and clinical research capabilities.

Business News

Industry news focusing on the people and organizations who work in the clinical trials profession.

Business and People Update January 2009

1. EUs Pediatric Regulation Sees First Approval: 

http://appliedclinicaltrialsonline.findpharma.com/appliedclinicaltrials/Regulatory+News/EUs-Pediatric-Regulation-Sees-First-Approval/ArticleStandard/Article/detail/563284

http://appliedclinicaltrialsonline.findpharma.com/appliedclinicaltrials/Trial+Design+Articles/Pediatric-Policies-Grow-Up/ArticleStandard/Article/detail/439743?searchString=pediatric%20clinical%20trials

Sufficient pediatric information on medicines used in children should be available; thus, pediatric clinical research should be enhanced. This is a consensus on a global basis and is now considered a public health priority. An increasing number of clinical trials are expected due to emerging laws and guidelines and governmental support and funding.

Pharmaceutical companies are subject to market economy with assignment of limited resources to profitable products. Because the rules of market economy are not sufficient to create a demand in pediatric research, there is a need for societal intervention.

  The first effective measure addressing this issue was realized in 1997, when the Food and Drug Modernization Act (FDAMA) was adopted.  

 PHOTOGRAPHY: GETTY IMAGES ILLUSTRATION: PAUL A. BELCI 

The measures of FDAMA encouraged companies to conduct studies of certain therapies being used in pediatrics by providing an exclusivity incentive provision.

  Further regulations followed including the Pediatric Research Equity Act, enabling the FDA to force companies to study certain drugs in children.

Between 1998 and 2004, 253 studies were submitted to the FDA for pediatric exclusivity. Labeling changes were positive for 127 of the 253 studies (50%). As a result of these changes in regulations and legislation in the United States, more trials have been done in children in these five years than in the previous 30 and there has been an improvement in safety information as well as dose changes for pediatric prescribing.

On January 26, 2007, 10 years after FDAMA was adopted, the European Pediatric Regulation 1901/2006 came into force.

  This regulation obliges the pharmaceutical industry to conduct clinical trials with children but can be waived for medicines that are unlikely to benefit them. In some cases, studies may be deferred until the medicine has been authorized for use in adults. 

The manufacturers will be compensated by a six-month extension of the supplementary protection certificate for conducting the pediatric development. In addition, there are programs that fund the pediatric development of substances without a supplementary protection certificate. 

The directive 2001/20/EC on Good Clinical Practice was adopted on the EU level in April 2001 and was implemented in Germany in August 2004. The directive's aim was to simplify and harmonize administrative procedures governing trials to provide patient protection by setting pan-European legal standards. Furthermore, the directive takes specific concerns into account regarding clinical trials with children and specifies criteria for their protection as study patients.

The EU has set up regulations to improve the quality and quantity of pediatric clinical trials. But what are the issues of clinical research with children in practice? Pediatric clinics and the pharmaceutical industry are two of the main parties involved in the conduct of pediatric clinical trials. Therefore, the authors wanted to evaluate the experiences these two parties had when conducting pediatric clinical trials with children in Germany. Furthermore, the number of studies conducted in the past and present and the number of expected future studies was part of the evaluation. 

The results of the two surveys showed that the pharmaceutical companies' activity with regard to pediatric clinical research in Germany was constant from 2000 until the implementation of the clinical trials directive. Of the replying companies, 60.7% vs. 66.7% conducted at least one clinical trial with children in the questioned time frames. 

According to the results of both surveys, 18 companies conducted clinical trials with children. Each survey demonstrated an average of 32 performed studies annually. 

AGE GROUPS AND INDICATIONS STUDIED. Both surveys showed that the majority of studies were conducted with children (ages two to 11 years). Only a few studies were conducted with preterm and term infants. 

The companies were asked to choose from indications that were considered likely to be of interest for investigations in children. The number of the studies reported in the 2005 survey, which are linked to the number of marketing authorizations in pediatric indications, are shown in Figure 1. 

Studies vs. Marketing Authorizations for 2003 and 2004 

Concerning the recruitment of investigators for clinical trials with children the results of the two surveys were inhomogeneous. One-third of the respondents of the first survey in 2000 reported that they had some problems finding qualified investigators. In contrast, the second survey indicated that more than two-thirds of the companies found the recruitment of investigators difficult. 

Although only one company reported investigators who were not willing to expose children to the "stress" of a clinical trial, it was rather difficult to find investigators for trials with young children or for trials with pharmacokinetic blood sampling, according to the survey of 2005. In both surveys, a fractional lack of theoretical knowledge and practical experience concerning clinical trials with children on the investigators' part were mentioned. 

The companies were also asked to choose from factors that contribute to the success or failure of clinical trials with children. The results were relatively homogenous in both surveys. Almost all companies assessed their own good organization of the study as an important requirement. The investigators' financial compensation was of lowest importance for the feasibility of the trials (18% in 2000 vs. <1% in 2005). The results are shown in detail in Figure 2. 

According to both surveys, there were no specific precautions on the ethics committees' parts. The causes for rejection reported were age limit concerns, insufficient data from adults, certain safety concerns, and objections concerning the written subject information. The clinical trials directive, and hence the requirement of health authority approval, was implemented in Germany in August 2004. We assumed that the majority of studies would have started before the implementation and, therefore, the companies were not asked about their experiences with the health authorities. 

In order to gather information from the investigator's point of view, a similar survey among pediatric university clinics was conducted in 2007.

  The questionnaire was adapted for this survey,

  but basically covered the same aspects as the pharmaceutical industry survey. In February 2007, the questionnaire was sent to 68 pediatric departments in 31 university clinics in Germany. These 68 centers consist of 30 general pediatric departments, 14 departments of pediatric cardiology, nine departments of pediatric oncology, six departments of pediatric neurology, four departments of neonatology, two departments of pediatric psychiatry, two departments of pediatric nephrology, and one department for pediatric surgery. Pediatric university clinics were selected based on the assumption that clinical research activities are more likely conducted in academic settings. 

Despite several reminders, only 27% of the 68 pediatric centers responded (18 centers). Five centers replied that they would not participate due to lack of time. Most of the oncology departments did not participate because "nearly every patient" takes part in "therapy optimization studies"—a special term used in the oncology field. 

All 18 centers performed trials with children between 2004 and 2006. In total, 229 studies in 18 centers were reported. However, in the case of multicenter studies, it might be possible that the same trial was reported by more than one center. According to the responses from 16 centers that intended to conduct trials with minors in 2007 and 2008, a minimum of 124 studies were expected to be performed. 

With respect to new laws, guidelines, and government support, the authors expected an increased number of clinical trials in children. However, the figures indicated a decreased number in the future; although incomplete plans at the centers may be an explanation for the low figures. 

The two surveys among the pharmaceutical firms and literature sources indicate that the majority of clinical trials are conducted with older children (six to 18 years) rather than with younger ones. Few data on randomized trials with very young children (preterm infants and infants) is available.

  Data from this survey is limited due to the low number of responding departments. However, the results indicate that trials are performed in all age classes, including in the very young, with a focus on trials in cardiology and metabolic diseases. 

The majority of studies accounted for in this survey were investigator sponsored trials/investigator initiated trials (IST/IIT). Most of them are supported by the pharmaceutical industry. One-third of the centers reported that the outcomes of the trials conducted in their department would be used for an initial marketing authorization. More than half stated that the trial results are intended for an extension of the indication for children. Most of these clinical trials were conducted with medicinal products already registered in adults or for other indications. 

A similar multiple-choice part assessing reasons for the success or failure of clinical trials was part of this questionnaire, with factors adjusted for the investigator's perspective. Most of the centers (10 of 18) named good coordination by their center as the predominant factor for the trial's success. Only five centers considered good organization by the pharma company responsible for the success of the study. In contrast, almost all companies considered their good organization as a requirement. 

It should be noted that most of the studies reported by the centers are ISTs/IITs. Thus, no organization by the pharmaceutical industry is needed. In opposition to the results of the company surveys, 22% of the responders (four of 18) cited the rate of the investigator's fee as a reason for the good conduct of the trial. Complete results on feasibility are shown in Figure 3. 

Investigators Points of View on Contributing Factors to Study Success 

The results of both surveys conducted within the pharmaceutical industry were confirmed by each other. Furthermore, the survey undertaken within German university departments shows similar results: 89% (16 of 18) of the centers answered that none of their clinical trials were refused by the ethics committees or health authorities. Only one center (one of 18) had experience where one project was refused. This could demonstrate high-quality study preparation (e.g., quality of medicinal product, study design, study protocol, informed consent) as well as a good collaboration with the ethics committees and health authorities. 

The EU regulation on medicinal products for pediatric use set up carrot-and-stick measures for the pharmaceutical industry. Hence, the number of industry sponsored trials with minors should increase, as it did according to the measures set up by the United States.  

The three surveys consulted with the pharmaceutical industry and investigators, and therefore adequately mirror pediatric clinical research in Germany from 2001 to 2008. The results of both surveys conducted within the pharmaceutical industry were confirmed by each other. Furthermore, the survey undertaken within German university departments shows similar results. According to these results, the Clinical Trials Directive (2001/20/EG) implemented in Germany in 2004 has had no effect on the number of trials performed in Germany in the pediatric population so far. 

Of course, as it is normal in surveys, limitations with respect to the number of participating companies and university clinics has to be considered. In both pharma surveys the response rate was very good compared to the response rate of the investigational sites. Nevertheless, a broad spectrum in the pediatric field is represented. 

One may conclude from the results of our surveys that the pharmaceutical industry is more interested in pediatric clinical research than the pediatricians. However, the regulation focuses on clinical research carried out by the pharmaceutical industry, whereas pediatric IST/IIT are not in the scope of this legislation. The future of investigator sponsored trials is uncertain since the new regulations make them more complex and expensive. Investigators are afraid that the high administrative efforts associated with the directive and the enormous trial costs make IST/IIT almost impossible.

Feature Article

Surveys among pharma, clinics, and investigators shed light on trials in children.

Pediatric Research in Germany

With greater attention and acceptance of biomarker use in clinical trials, the Society of Nuclear Medicine (SNM) is hoping to capitalize on its expertise in this area through the creation of the SNM Clinical Trials Network. The basic model of the Network is to utilize imaging biomarkers in conventional drug development through multicenter clinical trials offering standardized protocols across qualified sites.

Launched in early October, the network has been in continuous discussions with FDA during the past two years on issues related to biomarker use in clinical trials. In September, it received approval for the first multicenter centralized IND for F-18 fluorothymidine (FLT). FLT-18 is an investigational PET imaging biomarker that may be effective in measuring tumor proliferation as a surrogate marker for novel cancer therapies. In December, 

 published an article where researchers noted that "PET finds more areas of active cancer than other imaging tools..." Active clinical trials utilizing FLT are expected to begin in 2009.

Robert W. Atcher, PhD, MBA, president of SNM, told 

, the fundamental question is how does one use a surrogate marker to aid in development of new drugs? "Currently, the effectiveness of the drug is based on tumor volume, whether it is increasing, decreasing or staying the same. It is crude, given the tools we have," said Atcher. "If you use FLT, the tumor marker of cell proliferation, you are measuring to see if the cells are reproducing. You can see the change much more quickly [in cell proliferation vs. tumor volume]." 

Using biomarkers is not traditional, and the FDA's commitment is pivotal. In regard to the network, pharmaceutical companies will be able to cross-reference an SNM-sponsored centralized IND for multicenter trials via the Biomarker Use Pathway. The use of biomarkers in trials can demonstrate drug safety and efficacy more efficiently if included in the protocols, according to Atcher. In addition to working closely with FDA and the pharmaceutical company in the trial design process, SNM has started a clinical trial registry of sites that will adhere to SNM standards to assure imaging consistency in multicenter trials.

For industry, the first step in using imaging biomarkers is recognizing that sites image differently. The information is not standardized or measured the same across the sites. "They may have one site using an imaging agent. A single site in a fairly early stage of development positions them so they can expand out to Phase II use," explained Atcher. "But our network leads by providing access to the multicenter IND and ensuring that all the sites are utilizing the same protocol. You have all of the sites screened by some mechanism so they are engaged identically in the imaging part of the drug." SNM sites have to pledge they are operating under the guidelines suggested by the organization. 

While the biomarker is only at the cusp of its potential in drug development, the imaging biomarker has a great future. According to an SNM release, immediate past president Alexander J. B. McEwan, MD, said, "We believe the network will stimulate the development of additional novel imaging biomarkers. Therapeutic drug development trials using novel imaging biomarkers can also ultimately serve as surrogate parents for these nonproprietary probes. Simultaneously, drug development time can be reduced."

"These imaging biomarkers are of primary use in the development of oncology drugs," said Atcher. "But moving forward, the companies participating on advisory committees will contribute to the next compound for application for a multicenter IND. To date, SNM is focusing on those compounds that do not provide patent protection because they have been in use too long. If the company elects to utilize a proprietary agent that the company has licensed or developed itself, they have the option of accessing the trials network, as well. It's a parallel path," explained Atcher.—

News

With greater attention and acceptance of biomarker use in clinical trials, the Society of Nuclear Medicine (SNM) is hoping to capitalize on its expertise in this area through the creation of the SNM Clinical Trials Network.

Imaging Biomarker Network

Serious adverse event (SAE) reporting and to a lesser extent adverse event (AE) reporting have long been time consuming, costly, and often perplexing tasks for investigative sites. Growing worldwide concern about patient safety in clinical trials now seems to be unintentionally adding to the burden—with marginal to no real utility in improving subject protection.  

Many sponsors have begun seeking definitive answers from investigators about whether or not an AE or SAE is related to a study drug, an opinion that even the most astute clinician will admit comes down to guesswork. Institutional review boards (IRB) are also asserting themselves with information requests connected to protocol deviations and Investigational New Drug (IND) safety reports.  

Growing reporting requirements for SAEs and protocol deviations are widely considered by investigative sites to be distracting layers of bureaucracy at a time when they are expected to provide substantially higher levels of efficiency. Most sites believe study conduct performance targets cannot be met unless the burden of safety reporting can be eased. 

Sites understand the necessity of AE and SAE reporting and the federal requirements behind it. Investigative sites tacitly submit to the volume of exchanges with study sponsors and IRBs that these requirements require. Nonetheless, safety reporting is a very frustrating task, due in part to poor clarity around the definition of unexpected adverse events; the unpredictable frequency of SAEs; a lack of context with which to place the observed SAEs. 

The time investment for investigative sites to meet safety reporting requirements is anecdotally substantial. Study coordinators estimate that AE/SAE reporting consumes between 10% and 20% of their work effort on trials. These back-of-the-envelope estimates vary widely by therapeutic area. Little to no data has been systematically gathered to quantify the magnitude of this burden. But speak with any investigative site, and you'll get an ear full. 

Consider the case of the Alaska Clinical Research Center in Anchorage. "We're involved in a large Phase II trial that was supposed to have few side effects and we've had two SAEs so far," says Mary Anderson, RN, study coordinator and regulatory affairs manager. "You just never know when someone is going to have a severe allergic reaction or cardiac rhythm change." 

For one of the SAEs that occurred with the current oncology trial, Anderson figures she has spent 20 hours treating and monitoring the subject, scheduling procedures, picking up the patient's records from the hospital, and completing all the requisite paperwork, often in triplicate. The other SAE consumed less than five hours of her time to document, she says, because the subject was acutely ill and died of natural causes. 

When an SAE occurs, an initial two to five page SAE form must be filled in and sent to the study sponsor within 24 hours, as required by the FDA, and sites have much of the requested information on hand. But for weeks thereafter, the effected subject requires vigilant supervision. Sponsors also ask for regular updates on the patient's status and follow-up lab work until the SAE is resolved, as well as clarification on anything it deems inappropriate in the initial report. 

Although sponsors may be loath to hear it, sites know that accurate and timely reporting isn't always possible. With AEs, reporting is straightforward. It gets listed in a log, indicating when it started and was resolved, what action (if any) was taken, its severity and potential association with the study drug, and the outcome. "It's no problem," says Anderson, "as long as you know the answers. The primary issue is that patients don't always remember the precise day and time their symptoms began." 

"Recently, a female subject in a study waited until her 30-day follow-up visit to mention that she experienced hair loss during the entire study. Other times, an AE is discovered only because the complaint was voiced to another doctor and appears as a note on the patient's chart, often devoid of details such as date of the reported illness," she said. 

Cancer patients tend to be more conscientious about recording their symptoms, but oncology trials are particularly tricky when it comes to teasing out cause and effect. Overall, Anderson estimates that AE/SAE reporting consumes about 15% of her work hours but nearly a quarter of her time as a study coordinator.  

At Jasper Summit Research in Jasper, AL, which primarily conducts respiratory research, study coordinator Becky Thompson, RN, CCRC, says that AE/SAE reporting consumes less than 5% of her time on most studies.  

A bigger issue for some sites has been the growing role of IRBs in patient safety reporting over the past several years. Sites are required to report promptly to the IRB all protocol deviations, SAEs, and any other unanticipated problems involving risk to study subjects. Not only do sites face a deluge of reports that must be forwarded to IRBs, there are also no universal standards for reporting. 

"Each IRB has its own set of standards about what has to be reported to them," says Phillip D. Toth, MD, FACP, owner and medical director of the Midwest Institute for Clinical Research in Indianapolis, IN. "So sites are in a quandary as to what is reportable, such as when the patient misses a dose or is late by a week for a study visit." 

Dr. Toth and other principal investigators (PIs) believe that relative to all other safety-related reporting activities, dealing with protocol deviations represents the largest amount of paperwork with the least amount of clarity about what PIs should be doing. "This is time consuming and it doesn't serve the patient at all," says Toth. 

Most investigators believe at the heart of the matter lies the apparent distrust that IRBs have for research centers' ability to determine when a patient's safety is in jeopardy. "But IRBs unreservedly rely on sites' judgment when it comes to deciding if consent forms need amending based on IND safety reports sent out by sponsors," points out Toth. 

"Sites are actually solicited by IRBs for advice regarding needed changes to consent forms," says Toth. "When I submit a copy of the IND safety report to the IRB, I routinely ask for its counsel on the matter. But at best, the IRB will say it 'received' the IND safety report. It's rare for the IRB to say it has read the report or that it makes a recommendation regarding edits to the consent form." 

With some longer studies now generating as many as 100 IND safety reports, many investigators believe that IRBs are avoiding, even shirking, a major responsibility to ensure the consent form truthfully covers important information—and in plain language—about the clinical trial. 

In April 2007, the FDA issued a draft guidance for clinical investigators, sponsors, and IRBs entitled "Adverse Event Reporting—Improving Human Subject Protections." This draft guidance describes how the increasing use of multisite studies and international trials has "complicated the reporting pathways prescribed in regulations." The need for the guidance arose in 2005 due to IRBs complaining that they were receiving an increasingly large volume of individual AE reports often lacking the necessary context and detail for them to adequately address the complaints. 

The FDA has proposed more detailed definitions of what constitutes "unanticipated problems" and has recommended steps for study sponsors to aggregate and centralize the AE and SAE reporting process in order to ease the burden on IRBs. It is unclear whether this proposed arrangement will ultimately provide relief for investigative sites. However, at this time many investigators state that only a small number of sponsors are even aware that the now 20-month-old draft guidance is being considered. 

Most sites feel helpless to change the situation. A few have reported that they are considering requiring additional compensation from sponsors—between $500 and $750 per safety occurrence, for example—in order to make it easier to tolerate the burden of safety reporting. This is hardly a direction that sponsors would be receptive to given their need for ever-tighter cost controls. 

Ongoing patient education about the need to immediately report symptom changes and adverse reactions is a critically important step that can be taken by all study personnel at the outset of clinical trials.  

Recently, the Clinical Trials Transformation Initiative (CTTI), a broadly based consortium of stakeholders focusing on improving the trials process, proposed conducting a study designed to gather empirical evidence on the nature and magnitude of the problem and to propose viable relief. Clearly there is a need for such a study to inform sponsors, IRBs, and regulatory agencies about the huge and potentially unreasonable safety reporting burden that they are placing on investigative sites. Ultimately, this burden potentially harms patient safety instead of helping it. 

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

Clinical Trial Insights

A look at the vague but time consuming requirements imposed on sites and efforts to ease the burden.

Burying Sites Under Safety Reporting

Rater reliability is the cornerstone of data accuracy for drug trials that depend on clinician-rated subjective instruments to assess efficacy. Every pharmaceutical company seeks unambiguous evidence that its product is the new best treatment for a given disorder. Increasing governmental scrutiny of new drug applications combined with rising costs of product development and rising industry competition are pushing companies to improve the margin of success for their clinical trials. 

Demonstrating efficacy requires a confluence of excellence across multiple areas of clinical trial design and implementation. Protocol design issues, clinical features of the targeted disorder, the effectiveness of the drug, and study implementation factors all interact to affect signal detection. Pharmaceutical companies must consider all of these areas with meticulous attention to effectively demonstrate a significant drug effect. 

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